GRP119 receptor agonists in methods of increasing bone mass and of treating osteoporosis and other conditions characterized by low bone mass, and combination therapy relating thereto

ABSTRACT

The present invention relates to the use of GPR119 receptor agonists for treating or preventing a condition characterized by low bone mass, such as osteoporosis, and for increasing bone mass in an individual. The present invention further relates to the use of a GPR119 receptor agonist in combination with a dipeptidyl peptidase IV (DPP-IV) inhibitor for treating or preventing a condition characterized by low bone mass, such as osteoporosis, and for increasing bone mass in an individual. A GPR119 receptor agonist and the combination of a GPR119 receptor agonist and a DPP-IV inhibitor promote bone formation in an individual.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a national phase filing under 35 U.S.C. §371 ofInternational Application No. PCT/US2007/008926, filed on Apr. 10, 2007,which claims the benefit of priority of U.S. Application Ser. Nos.60/791,613, filed on Apr. 11, 2006; 60/834,737 filed Jul. 31, 2006; and60/851,244 filed Oct. 12, 2006. The disclosures of the priorapplications are considered part of (and are incorporated by referencein) the disclosure of this application.

FIELD OF THE INVENTION

The present invention relates to the use of GPR119 receptor agonists fortreating or preventing a condition characterized by low bone mass, suchas osteoporosis, and for increasing bone mass in an individual. Thepresent invention further relates to the use of a GPR119 receptoragonist in combination with a dipeptidyl peptidase IV (DPP-IV) inhibitorfor treating or preventing a condition characterized by low bone mass,such as osteoporosis, and for increasing bone mass in an individual. AGPR119 receptor agonist and the combination of a GPR119 receptor agonistand a DPP-IV inhibitor promote bone formation in an individual.

BACKGROUND OF THE INVENTION

The following discussion is intended to facilitate the understanding ofthe invention, but is not intended nor admitted to be prior art to theinvention.

A. Osteoporosis

Osteoporosis is a disabling disease characterized by the loss of bonemass and microarchitectural deterioration of skeletal structure leadingto compromised bone strength, which predisposes a patient to increasedrisk of fragility fractures. Osteoporosis affects more than 75 millionpeople in Europe, Japan and the United States, and causes more than 2.3million fractures in Europe and the United States alone. In the UnitedStates, osteoporosis affects at least 25% of all post-menopausal whitewomen, and the proportion rises to 70% in women older than 80 years. Onein three women older than 50 years will have an osteoporotic fracturethat causes a considerable social and financial burden on society. Thedisease is not limited to women; older men also can be affected. By2050, the worldwide incidence of hip fracture in men is projected toincrease by 310% and 240% in women. The combined lifetime risk for hip,forearm, and vertebral fractures presenting clinically is around 40%,equivalent to the risk for cardiovascular disease. Osteoporoticfractures therefore cause substantial mortality, morbidity, and economiccost. With an ageing population, the number of osteoporotic fracturesand their costs will at least double in the next 50 years unlesseffective preventive strategies are developed. (See, e.g., Atik et al.,Clin Orthop Relat Res (2006) 443:19-24; Raisz, J Clin Invest (2005)115:3318-3325; and World Health Organization Technical Report Series 921(2003), Prevention and Management of Osteoporosis.)

B. Glucose-Dependent Insulinotropic Polypeptide (GIP)

Glucose-dependent insulinotropic polypeptide (GIP, also known as gastricinhibitory polypeptide) is a peptide incretin hormone of 42 amino acidsthat is released from duodenal endocrine K cells after meal ingestion.The amount of GIP released is largely dependent on the amount of glucoseconsumed. GIP has been shown to stimulate glucose-dependent insulinsecretion in pancreatic beta cells. GIP mediates its actions through aspecific G protein-coupled receptor, namely GIPR.

As GIP contains an alanine at position 2, it is an excellent substratefor dipeptidyl peptidase-4 (DPP-IV), an enzyme regulating thedegradation of GIP. Full-length GIP(1-42) is rapidly converted tobioinactive GIP(3-42) within minutes of secretion from the gut K cell.Inhibition of DPP-IV has been shown to augment GIP bioactivity. (See,e.g., Drucker, Cell Metab (2006) 3:153-165; McIntosh et al., Regul Pept(2005) 128:159-165; Deacon, Regul Pept (2005) 128:117-124; and Ahren etal., Endocrinology (2005) 146:2055-2059). Analysis of full lengthbioactive GIP, for example in blood, can be carried out usingN-terminal-specific assays (see, e.g., Deacon et al, J Clin EndocrinolMetab (2000) 85:3575-3581).

Recently, GIP has been shown to promote bone formation. GIP has beenshown to activate osteoblastic receptors, resulting in increases incollagen type I synthesis and alkaline phosphatase activity, bothassociated with bone formation. GIP has been shown to inhibit osteoclastactivity and differentiation in vitro. GIP administration has been shownto prevent the bone loss due to ovariectomy. GIP receptor (GIPR)knockout mice evidence a decreased bone size, lower bone mass, alteredbone microarchitecture and biochemical properties, and alteredparameters for bone turnover, especially in bone formation. (See, e.g.,Zhong et al, Am J Physiol Endocrinol Metab (2007) 292:E543-E548; Bollaget al., Endocrinology (2000) 141:1228-1235; Bollag et al.; Mol CellEndocrinol (2001) 177:35-41; Xie et al., Bone (2005) 37:759-769; andTsukiyama et al., Mol Endocrinol (2006) 20:1644-1651.)

The usefulness of GIP for maintaining or increasing bone density orformation has been acknowledged by the United State Trademark and PatentOffice by issuance of U.S. Pat. No. 6,410,508 for the treatment ofreduced bone mineralization by administration of GIP peptide. However,current GIP peptide agonists suffer from a lack of oral bioavailability,negatively impacting patient compliance. An attractive alternativeapproach is to develop an orally active composition for increasing anendogenous level of GIP activity.

C. GPR119

GPR119 is a G protein-coupled receptor (GPR119; e.g., human GPR119,GenBank® Accession No. AAP72125 and alleles thereof; e.g., mouse GPR119,GenBank® Accession No. AY288423 and alleles thereof). GPR119 activationas by an agonist leads to elevation of the level of intracellular cAMP,consistent with GPR119 being coupled to Gs. In the patent literature,GPR119 has been referred to as RUP3 (e.g., International Application No.PCT/US99/23687); GPR119 has also been referred to as Glucose-DependentInsulinotropic Receptor (GDIR).

D. Dipeptidyl Peptidase IV (DPP-IV)

Dipeptidyl peptidase IV (DPP-IV, EC 3.4.14.5) exhibits catalyticactivity against a broad range of peptide substrates that includespeptide hormones, neuropeptides, and chemokines. The incretinsglucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropicpolypeptide (GIP), which stimulate glucose-dependent insulin secretionand otherwise promote blood glucose homeostasis, are rapidly cleaved byDPP-IV at the position 2 alanine leading to inactivation of theirbiological activity. Both pharmacological and genetic attenuation ofDPP-IV activity are associated with enhanced incretin action in vivo. Asecond-generation DPP-IV inhibitor, LAF237 (vildagliptin) (Ahren et al.,J Clin Endocrinol Metab (2004) 89:2078-2084; and Villhauer et al., J MedChem (2003) 46:2774-2789; the disclosure of each of which is hereinincorporated by reference in its entirety), is currently in phase 3clinical trials for Type 2 diabetes and additional DPP-IV inhibitors arein clinical development, including MK-0431 (sitagliptin), BMS-477118(saxagliptin), PSN-9301, T-6666, PHX-1149 and SYR-322 (alogliptin).Sitagliptin (Januvia™; sitagliptin phosphate) has recently been approvedby the U.S. Food and Drug Administration for use to improve blood sugarlevels in patients with Type 2 diabetes.

Because the incretin hormones are not the only substrates for DPP-IV,there is concern that inhibition of the cleavage of other endogenousDPP-IV substrates may give rise to undesirable side effects (see, e.g.,Chen et al, J Biol Regul Homeost Agents (2004) 18:47-54, the disclosureof which is herein incorporated by reference in its entirety). Ittherefore would be advantageous to identify a means for achievingincreased levels of endogenous GIP activity independently of using aDPP-IV inhibitor or by using substantially lower concentrations ofDPP-IV inhibitor than are presently contemplated.

SUMMARY OF THE INVENTION

The present invention relates to the unexpected discovery by Applicantthat administration of a GPR119 agonist, such as by oral administration,can act at GPR119 receptor to increase a GIP level in an individual.Applicant has further shown that a GPR119 agonist in combination with adipeptidyl peptidase IV (DPP-IV) inhibitor can provide an effect inincreasing a GIP level in an individual over that provided by the DPP-IVinhibitor alone. The present invention concerns a GPR119 agonist as wellas a combination of an amount of a GPR119 agonist with an amount ofDPP-IV inhibitor such that the combination provides an effect inincreasing a GIP level in an individual over that provided by the amountof the GPR119 agonist or the amount of the DPP-IV inhibitor alone. Thepresent invention further concerns the use of a GPR119 agonist and theuse of the combination of a GPR119 agonist with a DPP-IV inhibitor fortreating or preventing a condition characterized by low bone mass, suchas osteoporosis, and for increasing bone mass in an individual. A GPR119agonist alone or in combination with a DPP-IV inhibitor is useful forpromoting (e.g., increasing) bone formation in an individual. In certainembodiments, the individual is a human.

In a first aspect, the present invention features a method of treatingor preventing a condition characterized by low bone mass comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a composition comprising a GPR119 agonist. Thepresent invention additionally features a method of treating orpreventing a condition characterized by low bone mass comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a pharmaceutical composition comprising a GPR119agonist and a pharmaceutically acceptable carrier. In certainembodiments, the condition characterized by low bone mass is selectedfrom the group consisting of osteopenia, osteoporosis, rheumatoidarthritis, osteoarthritis, periodontal disease, alveolar bone loss,osteotomy bone loss, childhood idiopathic bone loss, Paget's disease,bone loss due to metastatic cancer, osteolytic lesions, curvature of thespine, and loss of height. In certain embodiments, the conditioncharacterized by low bone mass is osteoporosis. In certain embodiments,osteoporosis is primary osteoporosis. In certain embodiments,osteoporosis is secondary osteoporosis.

The present invention features a method of increasing bone masscomprising administering to an individual in need thereof atherapeutically effective amount of a composition comprising a GPR119agonist. The present invention additionally features a method ofincreasing bone mass comprising administering to an individual in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a GPR119 agonist and a pharmaceuticallyacceptable carrier. In certain embodiments, the individual in need ofincreased bone mass has a bone mineral density (BMD) greater than 1(T-score<−1) or greater than or equal to 1.5 (T-score≦−1.5), 2(T-score≦−2) or 2.5 (T-score≦−2.5) standard deviations below the youngadult reference mean. In certain embodiments, the individual in need ofincreased bone mass is in need of treatment of bone fracture. In certainembodiments, the individual has a traumatic bone fracture, a long-termbone fracture, or an osteoporotic fracture. In certain embodiments, theindividual in need of increased bone mass is in need of treatment of abone disease. In certain embodiments, the bone disease is selected fromthe group consisting of osteopenia, osteoporosis, rheumatoid arthritis,osteoarthritis, periodontal disease, alveolar bone loss, osteotomy boneloss, childhood idiopathic bone loss, Paget's disease, bone loss due tometastatic cancer, osteolytic lesions, curvature of the spine, and lossof height. In certain embodiments, the bone disease is osteoporosis. Incertain embodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis. In certainembodiments, the individual in need of increased bone mass is in need ofenhanced bone healing following facial reconstruction, maxillaryreconstruction, mandibular reconstruction, periodontal disease or toothextraction, enhanced long bone extension, enhanced prosthetic ingrowthor increased bone synostosis.

In certain embodiments, the GPR119 agonist is a selective GPR119agonist. In certain embodiments, the GPR119 agonist is selected from theleft column of Table D.

In certain embodiments, the administering is oral.

In certain embodiments, the GPR119 agonist is administered in an amountsufficient to increase a GIP level in the individual. In certainembodiments, the GIP level is a blood or plasma total GIP level. Incertain embodiments, the GIP level is a blood or plasma bioactive GIPlevel.

In certain embodiments, the individual is a vertebrate. In certainembodiments, the individual is a mammal. In certain embodiments, theindividual is a human.

In certain embodiments, the administering is carried out in a singledose.

In certain embodiments, the individual is not a human and theadministering is carried out in a single dose.

In certain embodiments, the administering is carried out in multipledoses over a period of greater than 24 days, greater than 36 days,greater than 48 days or greater than 60 days. In certain embodiments,the multiple doses are consecutive daily doses. In certain embodiments,the individual is not a human and the administering is carried out inmultiple doses over a period of greater than 24 days, greater than 36days, greater than 48 days or great than 60 days. In certainembodiments, the individual is not a human and the multiple doses areconsecutive daily doses.

In certain embodiments, the individual is a human and the administeringis carried out in a single dose.

In certain embodiments, the individual is a human and the administeringis carried out in consecutive daily doses over a period of at least 2days, at least 7 days, at least 14 days, at least 30 days or at least 60days.

In certain embodiments, the individual is a human and the administeringis carried out in multiple doses over a period of greater than 8 weeks,greater than 12 weeks, greater than 16 weeks, greater than 20 weeks,greater than 24 weeks, greater than 28 weeks, greater than 32 weeks orgreater than 36 weeks. In certain embodiments, the multiple doses areconsecutive daily doses.

In a second aspect, the present invention features use of a GPR119agonist to treat a condition characterized by low bone mass in the humanor animal body by therapy. In certain embodiments, the human or animalbody is a human body. In certain embodiments, the conditioncharacterized by low bone mass is selected from the group consisting ofosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height.In certain embodiments, the condition characterized by low bone mass isosteoporosis. In certain embodiments, osteoporosis is primaryosteoporosis. In certain embodiments, osteoporosis is secondaryosteoporosis.

The present invention features use of a GPR119 agonist to increase bonemass in the human or animal body by therapy. In certain embodiments, thehuman or animal body is a human body. In certain embodiments, the humanor animal body has a bone mineral density (BMD) greater than 1(T-score<−1) or greater than or equal to 1.5 (T-score≦−1.5), 2(T-score≦−2) or 2.5 (T-score≦−2.5) standard deviations below the youngadult reference mean. In certain embodiments, the human or animal bodyis in need of treatment of bone fracture. In certain embodiments, thehuman or animal body has a traumatic bone fracture, a long-term bonefracture, or an osteoporotic fracture. In certain embodiments, the humanor animal body is in need of treatment of a bone disease. In certainembodiments, the bone disease is selected from the group consisting ofosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height.In certain embodiments, the bone disease is osteoporosis. In certainembodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis. In certainembodiments, the human or animal body is in need of enhanced bonehealing following facial reconstruction, maxillary reconstruction,mandibular reconstruction, periodontal disease or tooth extraction,enhanced long bone extension, enhanced prosthetic ingrowth or increasedbone synostosis.

In certain embodiments, the GPR119 agonist is a selective GPR119agonist. In certain embodiments, the GPR119 agonist is selected from theleft column of Table D.

In certain embodiments, the GPR119 agonist is provided in an amountsufficient to increase a GIP level in the human or animal body. Incertain embodiments, the GIP level is a blood or plasma total GIP level.In certain embodiments, the GIP level is a blood or plasma bioactive GIPlevel.

In certain embodiments, the human or animal body is a human body.

In a third aspect, the present invention features use of a GPR119agonist for the manufacture of a medicament for the treatment orprevention of a condition characterized by low bone mass in anindividual. In certain embodiments, the condition characterized by lowbone mass is selected from the group consisting of osteopenia,osteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease,alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss,Paget's disease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, and loss of height. In certain embodiments, thecondition characterized by low bone mass is osteoporosis. In certainembodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis.

The present invention features use of a GPR119 agonist for themanufacture of a medicament for increasing bone mass in an individual.In certain embodiments, the individual has a bone mineral density (BMD)greater than 1 (T-score<−1) or greater than or equal to 1.5(T-score≦−1.5), 2 (T-score≦−2) or 2.5 (T-score≦−2.5) standard deviationsbelow the young adult reference mean. In certain embodiments, theindividual is in need of treatment of bone fracture. In certainembodiments, the individual has a traumatic bone fracture, a long-termbone fracture, or an osteoporotic fracture. In certain embodiments, theindividual is in need of treatment of a bone disease. In certainembodiments, the bone disease is selected from the group consisting ofosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height.In certain embodiments, the bone disease is osteoporosis. In certainembodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis. In certainembodiments, the individual is in need of enhanced bone healingfollowing facial reconstruction, maxillary reconstruction, mandibularreconstruction, periodontal disease or tooth extraction, enhanced longbone extension, enhanced prosthetic ingrowth or increased bonesynostosis.

In certain embodiments, the GPR119 agonist is a selective GPR119agonist. In certain embodiments, the GPR119 agonist is selected from theleft column of Table D.

In certain embodiments, the GPR119 agonist is provided in an amountsufficient to increase a GIP level in the individual. In certainembodiments, the GIP level is a blood or plasma total GIP level. Incertain embodiments, the GIP level is a blood or plasma bioactive GIPlevel.

In certain embodiments, the individual is a vertebrate. In certainembodiments, the individual is a mammal. In certain embodiments, theindividual is a human.

In a fourth aspect, the present invention features a method of treatingor preventing a condition characterized by low bone mass comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a composition comprising a GPR119 agonist and aDPP-IV inhibitor. The present invention additionally features a methodof treating or preventing a condition characterized by low bone masscomprising administering to an individual in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprising a GPR119 agonist and a DPP-IV inhibitor and apharmaceutically acceptable carrier. In certain embodiments, thecondition characterized by low bone mass is selected from the groupconsisting of osteopenia, osteoporosis, rheumatoid arthritis,osteoarthritis, periodontal disease, alveolar bone loss, osteotomy boneloss, childhood idiopathic bone loss, Paget's disease, bone loss due tometastatic cancer, osteolytic lesions, curvature of the spine, and lossof height. In certain embodiments, the condition characterized by lowbone mass is osteoporosis. In certain embodiments, osteoporosis isprimary osteoporosis. In certain embodiments, osteoporosis is secondaryosteoporosis.

The present invention features a method of increasing bone masscomprising administering to an individual in need thereof atherapeutically effective amount of a composition comprising a GPR119agonist and a DPP-IV inhibitor. The present invention additionallyfeatures a method of increasing bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of apharmaceutical composition comprising a GPR119 agonist and a DPP-IVinhibitor and a pharmaceutically acceptable carrier. In certainembodiments, the individual in need of increased bone mass has a bonemineral density (BMD) greater than 1 (T-score<−1) or greater than orequal to 1.5 (T-score≦−1.5), 2 (T-score≦−2) or 2.5 (T-score≦−2.5)standard deviations below the young adult reference mean. In certainembodiments, the individual in need of increased bone mass is in need oftreatment of bone fracture. In certain embodiments, the individual has atraumatic bone fracture, a long-term bone fracture, or an osteoporoticfracture. In certain embodiments, the individual in need of increasedbone mass is in need of treatment of a bone disease. In certainembodiments, the bone disease is selected from the group consisting ofosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height.In certain embodiments, the bone disease is osteoporosis. In certainembodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis. In certainembodiments, the individual in need of increased bone mass is in need ofenhanced bone healing following facial reconstruction, maxillaryreconstruction, mandibular reconstruction, periodontal disease or toothextraction, enhanced long bone extension, enhanced prosthetic ingrowthor increased bone synostosis.

In certain embodiments, the GPR119 agonist is a selective GPR119agonist. In certain embodiments, the GPR119 agonist is selected from theleft column of Table D.

In certain embodiments, the DPP-IV inhibitor is a selective DPP-IVinhibitor. In certain embodiments, the DPP-IV inhibitor is selected fromthe right column of Table D.

In certain embodiments, the GPR119 agonist is selected from the leftcolumn of Table D and the DPP-IV inhibitor is selected from the rightcolumn of Table D.

In certain embodiments, the administering is oral.

In certain embodiments, the GPR119 agonist or the combination of theGPR119 agonist and the DPP-IV inhibitor is administered in an amountsufficient to increase a GIP level in the individual. In certainembodiments, the GIP level is a blood or plasma total GIP level. Incertain embodiments, the GIP level is a blood or plasma bioactive GIPlevel.

In certain embodiments, the individual is a vertebrate. In certainembodiments, the individual is a mammal. In certain embodiments, theindividual is a human.

In certain embodiments, the administering is carried out in a singledose.

In certain embodiments, the individual is not a human and theadministering is carried out in a single dose.

In certain embodiments, the administering is carried out in multipledoses over a period of greater than 24 days, greater than 36 days,greater than 48 days or greater than 60 days. In certain embodiments,the multiple doses are consecutive daily doses. In certain embodiments,the individual is not a human and the administering is carried out inmultiple doses over a period of greater than 24 days, greater than 36days, greater than 48 days or great than 60 days. In certainembodiments, the individual is not a human and the multiple doses areconsecutive daily doses.

In certain embodiments, the individual is a human and the administeringis carried out in a single dose.

In certain embodiments, the individual is a human and the administeringis carried out in consecutive daily doses over a period of at least 2days, at least 7 days, at least 14 days, at least 30 days or at least 60days.

In certain embodiments, the individual is a human and the administeringis carried out in multiple doses over a period of greater than 8 weeks,greater than 12 weeks, greater than 16 weeks, greater than 20 weeks,greater than 24 weeks, greater than 28 weeks, greater than 32 weeks orgreater than 36 weeks.

In a fifth aspect, the present invention features use of a GPR119agonist in combination with a DPP-IV inhibitor to treat a conditioncharacterized by low bone mass in the human or animal body by therapy.In certain embodiments, the human or animal body is a human body. Incertain embodiments, the condition characterized by low bone mass isselected from the group consisting of osteopenia, osteoporosis,rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar boneloss, osteotomy bone loss, childhood idiopathic bone loss, Paget'sdisease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, and loss of height. In certain embodiments, thecondition characterized by low bone mass is osteoporosis. In certainembodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis.

The present invention features use of a GPR119 agonist in combinationwith a DPP-IV inhibitor to increase bone mass in the human or animalbody by therapy. In certain embodiments, the human or animal body is ahuman body. In certain embodiments, the human or animal body has a bonemineral density (BMD) greater than 1 (T-score<−1) or greater than orequal to 1.5 (T-score≦−1.5), 2 (T-score≦−2) or 2.5 (T-score≦−2.5)standard deviations below the young adult reference mean. In certainembodiments, the human or animal body is in need of treatment of bonefracture. In certain embodiments, the human or animal body has atraumatic bone fracture, a long-term bone fracture, or an osteoporoticfracture. In certain embodiments, the human or animal body is in need oftreatment of a bone disease. In certain embodiments, the bone disease isselected from the group consisting of osteopenia, osteoporosis,rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar boneloss, osteotomy bone loss, childhood idiopathic bone loss, Paget'sdisease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, and loss of height. In certain embodiments, thebone disease is osteoporosis. In certain embodiments, osteoporosis isprimary osteoporosis. In certain embodiments, osteoporosis is secondaryosteoporosis. In certain embodiments, the human or animal body is inneed of enhanced bone healing following facial reconstruction, maxillaryreconstruction, mandibular reconstruction, periodontal disease or toothextraction, enhanced long bone extension, enhanced prosthetic ingrowthor increased bone synostosis.

In certain embodiments, the GPR119 agonist is a selective GPR119agonist. In certain embodiments, the GPR119 agonist is selected from theleft column of Table D.

In certain embodiments, the DPP-IV inhibitor is a selective DPP-IVinhibitor. In certain embodiments, the DPP-IV inhibitor is selected fromthe right column of Table D.

In certain embodiments, the GPR119 agonist is selected from the leftcolumn of Table D and the DPP-IV inhibitor is selected from the rightcolumn of Table D.

In certain embodiments, the GPR119 agonist or the combination of aGPR119 agonist and the DPP-IV inhibitor is provided in an amountsufficient to increase a GIP level in the human or animal body. Incertain embodiments, the GIP level is a blood or plasma total GIP level.In certain embodiments, the GIP level is a blood or plasma bioactive GIPlevel.

In certain embodiments, the human or animal body is a human body.

In a sixth aspect, the present invention features use of a GPR119agonist in combination with a DPP-IV inhibitor for the manufacture of amedicament for the treatment or prevention of a condition characterizedby low bone mass in an individual. In certain embodiments, the conditioncharacterized by low bone mass is selected from the group consisting ofosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height.In certain embodiments, the condition characterized by low bone mass isosteoporosis. In certain embodiments, osteoporosis is primaryosteoporosis. In certain embodiments, osteoporosis is secondaryosteoporosis.

The present invention features use of a GPR119 agonist in combinationwith a DPP-IV inhibitor for the manufacture of a medicament forincreasing bone mass in an individual. In certain embodiments, theindividual has a bone mineral density (BMD) greater than 1 (T-score<−1)or greater than or equal to 1.5 (T-score≦−1.5), 2 (T-score≦−2) or 2.5(T-score≦−2.5) standard deviations below the young adult reference mean.In certain embodiments, the individual is in need of treatment of bonefracture. In certain embodiments, the individual has a traumatic bonefracture, a long-term bone fracture, or an osteoporotic fracture. Incertain embodiments, the individual is in need of treatment of a bonedisease. In certain embodiments, the bone disease is selected from thegroup consisting of osteopenia, osteoporosis, rheumatoid arthritis,osteoarthritis, periodontal disease, alveolar bone loss, osteotomy boneloss, childhood idiopathic bone loss, Paget's disease, bone loss due tometastatic cancer, osteolytic lesions, curvature of the spine, and lossof height. In certain embodiments, the bone disease is osteoporosis. Incertain embodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis. In certainembodiments, the individual is in need of enhanced bone healingfollowing facial reconstruction, maxillary reconstruction, mandibularreconstruction, periodontal disease or tooth extraction, enhanced longbone extension, enhanced prosthetic ingrowth or increased bonesynostosis.

In certain embodiments, the GPR119 agonist is a selective GPR119agonist. In certain embodiments, the GPR119 agonist is selected from theleft column of Table D.

In certain embodiments, the DPP-IV inhibitor is a selective DPP-IVinhibitor. In certain embodiments, the DPP-IV inhibitor is selected fromthe right column of Table D.

In certain embodiments, the GPR119 agonist is selected from the leftcolumn of Table D and the DPP-IV inhibitor is selected from the rightcolumn of Table D.

In certain embodiments, the GPR119 agonist or the combination of theGPR119 agonist and the DPP-IV inhibitor is provided in an amountsufficient to increase a GIP level in the individual. In certainembodiments, the GIP level is a blood or plasma total GIP level. Incertain embodiments, the GIP level is a blood or plasma bioactive GIPlevel.

In certain embodiments, the individual is a vertebrate. In certainembodiments, the individual is a mammal. In certain embodiments, theindividual is a human.

In a seventh aspect, the invention features a method according to thefirst aspect or to the fourth aspect, optionally further comprising thestep of identifying the individual as an individual judged by acaregiver to require or benefit from said treating or preventing acondition characterized by low bone mass or from said increasing bonemass, and optionally further comprising the step of identifyingachievement of therapeutic efficacy of said administering of saidcomposition or said pharmaceutical composition.

In certain embodiments, the invention features a method of the firstaspect, further comprising the step of identifying the individual as anindividual judged by a caregiver to require or benefit from saidtreating or preventing a condition characterized by low bone mass orfrom said increasing bone mass.

In certain embodiments, the invention features a method of the fourthaspect, further comprising the step of identifying the individual as anindividual judged by a caregiver to require or benefit from saidtreating or preventing a condition characterized by low bone mass orfrom said increasing bone mass.

In certain embodiments, the invention features a method of the firstaspect, further comprising the step of identifying achievement oftherapeutic efficacy of said administering of said composition or saidpharmaceutical composition.

In certain embodiments, the invention features a method of the fourthaspect, further comprising the step of identifying achievement oftherapeutic efficacy of said administering of said composition or saidpharmaceutical composition.

In certain embodiments, the invention features a method of the firstaspect, further comprising the step of identifying the individual as anindividual judged by a caregiver to require or benefit from saidtreating or preventing a condition characterized by low bone mass orfrom said increasing bone mass, and further comprising the step ofidentifying achievement of therapeutic efficacy of said administering ofsaid composition or said pharmaceutical composition.

In certain embodiments, the invention features a method of the fourthaspect, further comprising the step of identifying the individual as anindividual judged by a caregiver to require or benefit from saidtreating or preventing a condition characterized by low bone mass orfrom said increasing bone mass, and further comprising the step ofidentifying achievement of therapeutic efficacy of said administering ofsaid composition or said pharmaceutical composition.

In certain embodiments wherein the individual is a human, the caregiveris a physician, a nurse or a nurse practitioner. In certain embodimentswherein the individual is a non-human vertebrate, and in particularembodiment a non-human mammal, the caregiver is a veterinarian.

In certain embodiments, said identifying achievement of therapeuticefficacy of said administering comprises measuring a level of bone massin the individual. In certain embodiments, said measuring a level ofbone mass comprises measuring the level of bone mass using dual energyX-ray absorptiometry (DXA). In certain embodiments, said measuring alevel of bone mass using DXA comprises measuring a T-score using DXA. Incertain embodiments, said measuring a T-score using DXA comprisesmeasuring a T-score at the hip using DXA. It is expressly contemplatedthat said measuring a level of bone mass may comprise measuring a levelof bone mass using a technique other than DXA, such as single X-rayabsorbtiometry (SXA) [see, e.g., World Health Organization TechnicalReport Series 921 (2003), Prevention and Management of Osteoporosis].

In some embodiments, said identifying achievement of therapeuticefficacy of said administering comprises measuring a GIP level in theindividual. In certain embodiments, the GIP level is a blood or plasmatotal GIP level. In certain embodiments, the GIP level is a blood orplasma bioactive GIP level.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is illustrated in connection with the figures appendedhereto in which:

FIG. 1 shows a pharmacodynamic analysis of an effect of administrationof GPR119 agonist on blood GIP level in wild-type mice. A. A time courseanalysis carried out using Compound 1Z as the GPR119 agonist. B. A timecourse analysis carried out using Compound 3Z as the GPR119 agonist. C.A dose titration analysis carried out using Compound 3Z as the GPR119agonist.

FIG. 2 shows an effect of administration of GPR119 agonist on blood GIPlevel in GPR119-deficient (knockout) mice compared to wild-type mice. A.The comparison was carried out using Compound 1Z as the GPR119 agonist.B. The comparison was carried out using Compound 2Z as the GPR119agonist.

FIG. 3 shows an effect of administration of a DPP-IV inhibitor incombination with a GPR119 agonist compared with the DPP-IV inhibitoralone on blood GIP level in wild-type mice. Compound 1Z was used as theGPR119 agonist. AR247810 was used as the DPP-IV inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

This invention is concerned with certain compounds, or pharmaceuticallyacceptable salts thereof, for the treatment or prevention in anindividual of a condition characterized by low bone mass, such asosteoporosis. This invention is further concerned with certaincompounds, or pharmaceutically acceptable salts thereof, for increasingbone mass in an individual. Applicant has found that administering of aGPR119 agonist to an individual, such as by oral administration, canincrease a GIP level in the individual. A GPR119 agonist is useful fortreating or preventing a condition characterized by low bone mass, suchas osteoporosis, and for increasing bone mass in an individual.

This invention is concerned with the combination of certain compounds,or pharmaceutically acceptable salts thereof, for the treatment orprevention in an individual of a condition characterized by low bonemass, such as osteoporosis. This invention is further concerned with thecombination of certain compounds, or pharmaceutically acceptable saltsthereof, for increasing bone mass in an individual. An amount of aGPR119 agonist in combination with an amount of a DPP-IV inhibitor canprovide an effect in increasing a GIP level in an individual over thatprovided by the amount of the GPR119 agonist or the amount of the DPP-IVinhibitor alone. The combination of a GPR119 agonist and a DPP-IVinhibitor is useful for the treatment or prevention in an individual ofa condition characterized by low bone mass, such as osteoporosis. Thecombination of a GPR119 agonist and a DPP-IV inhibitor is useful forincreasing bone mass in an individual.

By the use of a combination of a GPR119 agonist and a DPP-IV inhibitorin accordance with the present invention, it is possible to treat orprevent a condition characterized by low bone mass more effectively thanby use of a GPR119 agonist or a DPP-IV inhibitor alone, thereby reducingthe likelihood of unwanted side-effects associated with inhibition ofDPP-IV activity. By the use of a combination of a GPR119 agonist and aDPP-IV inhibitor in accordance with the present invention, it ispossible to increase bone mass more effectively than by use of a GPR119agonist or a DPP-IV inhibitor alone, thereby reducing the likelihood ofunwanted side-effects associated with inhibition of DPP-IV activity. Thepresent invention provides new, unexpected and advantageous approachesto treating or preventing a condition characterized by low bone mass,such as osteoporosis, and to increasing bone mass in an individual. Thepresent invention additionally provides new, unexpected and advantageousapproaches to increasing a GIP level in an individual.

The term “ligand”, as used herein, shall mean a molecule (e.g., testcompound) that specifically binds to a polypeptide, such as GPR119 orDPP-IV. A ligand may be, for example, a polypeptide, a lipid, a smallmolecule, an antibody. Compound 1Z is an exemplary ligand of GPR119receptor polypeptide (see, Table E, which sets forth the chemicalstructure and chemical name of Compound 1Z). Compound 1Z is identical toa compound disclosed in International Patent Application No.PCT/US2004/001267 (published as WO 2004/065380).(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine(see, Table E) is an exemplary ligand of GPR119 receptor polypeptide.Compound 2Z is an exemplary ligand of GPR119 receptor polypeptide.Compound 2Z is identical to a compound disclosed in International PatentApplication No. PCT/US2004/022417 (published as WO 2005/007658).Compound 3Z is an exemplary ligand of GPR119 receptor polypeptide.Compound 3Z is identical to a compound disclosed in International PatentApplication No. PCT/US2004/022327 (published as WO 2005/007647). Anendogenous ligand is a ligand that is an endogenous, natural ligand fora native polypeptide, such as GPR119 or DPP-IV. A ligand may be an“antagonist”, “agonist”, “partial agonist”, or “inverse agonist”, or thelike. A ligand may be an “inhibitor.”

TABLE E

(2-Fluoro-4-methanesulfonyl- phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]- 5-nitro-pyrimidin-4-yl}-amine

The term “agonist”, as used herein, shall mean an agent (e.g., ligand)that by virtue of binding to a GPCR activates the GPCR so as to elicitan intracellular response mediated by the GPCR.

The term “partial agonist”, as used herein, shall mean an agent (e.g.,ligand) that by virtue of binding to a GPCR activates the GPCR so as toelicit an intracellular response mediated by the GPCR, albeit to alesser extent or degree than does a full agonist.

The term “antagonist” shall mean an agent (e.g., ligand) that binds, andin particular embodiment binds competitively, to a GPCR at about thesame site as an agonist or partial agonist but which does not activatean intracellular response initiated by the active form of the GPCR, andcan thereby inhibit the intracellular response by agonist or partialagonist. An anatagonist typically does not diminish the baselineintracellular response in the absence of an agonist or partial agonist.

The term “inverse agonist” shall mean an agent (e.g., ligand) whichbinds to a GPCR and which inhibits the baseline intracellular responseinitiated by the active form of the receptor below the normal base levelactivity which is observed in the absence of an agonist or partialagonist.

The term “GPR119 agonist,” as used herein, refers to a compound thatbinds to GPR119 receptor and acts as an agonist. Compound 1Z is anexemplary GPR119 agonist (see, Table E, which sets forth the chemicalstructure and chemical name of Compound 1Z). Compound 1Z is identical toa compound disclosed in International Patent Application No.PCT/US2004/001267 (published as WO 2004/065380).(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amineis an exemplary GPR119 agonist. Compound 2Z is an exemplary GPR119agonist. Compound 2Z is identical to a compound disclosed inInternational Patent Application No. PCT/US2004/022417 (published as WO2005/007658). Compound 3Z is an exemplary GPR119 agonist. Compound 3Z isidentical to a compound disclosed in International Patent ApplicationNo. PCT/US2004/022327 (published as WO 2005/007647).

The term “selective GPR119 agonist,” as used herein, refers to a GPR119agonist having selectivity for GPR119 receptor over one or more relatedreceptors, such as corticotrophin-releasing factor-1 (CRF-1) receptor.Compound 1Z is an exemplary selective GPR119 agonist (see, Table E,which sets forth the chemical structure and chemical name of Compound1Z). Compound 1Z is identical to a compound disclosed in InternationalPatent Application No. PCT/US2004/001267 (published as WO 2004/065380).(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amineis an exemplary selective GPR119 agonist. Compound 2Z is an exemplaryselective GPR119 agonist. Compound 2Z is identical to a compounddisclosed in International Patent Application No. PCT/US2004/022417(published as WO 2005/007658). Compound 3Z is an exemplary selectiveGPR119 agonist. Compound 3Z is identical to a compound disclosed inInternational Patent Application No. PCT/US2004/022327 (published as WO2005/007647).

The term “DPP-IV inhibitor,” as used herein, refers to a compound thatbinds to DPP-IV and inhibits DPP-IV dipeptidyl peptidase activity.AR247810 is an exemplary DPP-IV inhibitor.

The term “selective DPP-IV inhibitor,” as used herein, refers to aDPP-IV inhibitor having selectivity for DPP-IV over related peptidases,such as one or more of post-proline-cleaving enzyme (PPCE), dipeptidylpeptidase II (DPP-II), dipeptidyl peptidase 8 (DPP-8), and dipeptidylpeptidase 9 (DPP-9). AR247810 is an exemplary selective DPP-IVinhibitor.

The term “blood GIP level” shall mean blood GIP concentration. Incertain embodiments, a blood GIP level is a blood total GIP level. Incertain embodiments, a blood GIP level is a blood biologically active(bioactive) GIP level. In certain embodiments, bioactive GIP is GIPhaving agonist activity at GIPR. In certain embodiments, a blood GIPlevel is a plasma GIP level.

The term “individual,” as used herein, refers to a vertebrate, includingbut not limited to fish (such as commercially farmed fish, pet fish,etc.), amphibians (such as frogs, toads, pet amphibians, etc.), reptiles(such as snakes, lizards, turtles, pet reptiles, etc.), birds (such aschickens, turkeys, pet birds, etc.) and mammals (such as mice, rats,hamsters, rabbits, pigs, dogs, cats, horses, cows, sheep, goats,non-human primates, non-human mammals, pet non-human mammals, humans,etc.). In certain embodiments, the individual is a fish. In certainembodiments, the individual is an amphibian. In certain embodiments, theindividual is a reptile. In certain embodiments, the individual is abird. In certain embodiments, the individual is a turkey. Over the past25 yr, commercial selection pressure for turkeys with larger breastmuscle mass has placed increasing demands on skeletal integrity. Theincreased breast muscle mass, however, has not been accompanied bycompensatory changes in the skeleton, with the result that the turkeyindustry has experienced an increase in leg problems. Long bone fracturein young adult male turkeys has been reported. (See, e.g., Crespo et al,Poult Sci (2000) 79:602-608.) In certain embodiments, the individual isa mammal. In certain embodiments, the individual is a mouse, a rat, ahamster, a rabbit, a pig, a dog, a cat, a horse, a cow, a sheep, a goat,a non-human primate or a human (which may be included in embodiments ofthe invention individually or in any combination). In certainembodiments, the individual is a horse. Performance horses, which arehorses involved in activities such as racing, pacing and othercompetitive events, are susceptible to bone fracture. In certainembodiments, the individual is a dog or a cat. In certain embodiments,the individual is a human companion animal (such as a dog, a cat, etc.),a farm animal (such as a cow, a sheep, a goat, a pig, a chicken, etc.),a sports animal (such as a horse, a dog, etc.), a beast of burden (suchas a mule, a camel, etc.) or an exotic animal (such as an animal foundin a zoo, etc.), which may be included in embodiments of the inventionindividually or in any combination. In certain embodiments, theindividual is a non-human mammal. In certain embodiments, the individualis a non-human primate (such as a rhesus monkey, a chimpanzee, etc.). Incertain embodiments, the individual is a human.

The term “in need of prevention or treatment” as used herein refers to ajudgement made by a caregiver (e.g. physician, nurse, nurse practitionerin the case of humans; veterinarian in the case of non-humanvertebrates, and in particular embodiment non-human mammals) that anindividual requires or will benefit from treatment.

The term “therapeutically effective amount” or “therapeuticallyeffective dose” as used herein refers to the amount of active compoundor pharmaceutical agent that elicits the biological or medicinalresponse in a tissue, system, animal, individual or human that is beingsought by a researcher, veterinarian, medical doctor or other clinician,which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The term “therapeutic efficacy” as used herein refers to elicitation ofthe biological or medicinal response in a tissue, system, animal,individual or human that is being sought by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

The term “amount that is effective to prevent” refers to that amount ofdrug that will prevent or reduce the risk of occurrence of thebiological or medical event that is sought to be prevented. In manyinstances, the amount that is effective to prevent is the same as thetherapeutically effective amount.

The term “composition” shall mean a material comprising at least onecomponent.

The term “active ingredient” shall mean any component that providespharmacological activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease.

The term “pharmaceutical composition” shall mean a compositioncomprising at least one active ingredient, whereby the composition isamenable to investigation and treatment in a mammal.

By “pharmaceutically acceptable” it is meant that the carrier, vehicle,diluent, excipients, and/or salt must be compatible with the otheringredients of the formulation, and not deleterious to the recipientthereof.

The term “dosage form” shall mean the physical form in which a drug isproduced and dispensed, such as a tablet, capsule, or an injectable.

By “bone” is intended the dense, semi-rigid, porous, calcifiedconnective tissue forming the major portion of the skeleton of mostvertebrates, comprising a dense organic matrix and an inorganic, mineralcomponent. Bone is any of numerous anatomically distinct structuresmaking up the skeleton of a vertebrate.

The terms “bone mass” and “bone mineral density (BMD)” are usedinterchangeably herein. BMD in humans is usually measured by a standardradiographic technique, dual energy X-ray absorptiometry (DXA). Of themany techniques developed to assess BMD, DXA is the most highlydeveloped technically and the most thoroughly validated biologically.DXA technology, with suitably adapted software, can also be used toreliably assess BMD in animal studies. DXA is used in the diagnosis ofosteoporosis, prognosis (fracture prediction), monitoring the naturalhistory of the disorder, and assessing response to treatment.

The term “low bone mass” as used herein refers to any decrease orreduction in bone mineral density (BMD) in an individual, and includesboth osteoporosis and osteopenia as defined in proposals by the WorldHealth Organization (WHO). The WHO has defined normal as a value of BMDwithin one standard deviation of the young adult reference mean(T-score≧−1). The WHO has defined osteopenia as a value of BMD more than1 standard deviation below the young adult mean, but less than 2.5standard deviations below this value (T-score<−1 and >−2.5). The WHO hascharacterized osteoporosis as a more severe form of osteopenia, and hasdefined it by value of BMD 2.5 standard deviations or more blow theyoung adult mean (T-score ≦−2.5). (See, e.g., World Health OrganizationTechnical Report Series 921 (2003), Prevention and Management ofOsteoporosis, the disclosure of which is herein incorporated byreference in its entirety.) More commonly, osteopenia is defined as aT-score of less than −1 and greater than −2, and osteoporosis is definedas a T-score of less than or equal to −2. In certain embodiments of thepresent invention, the T-score is measured at the hip with DXA.

The term “osteoporosis” as used herein is defined by a value of BMD 2standard deviations or more below the young adult reference mean(T-score≦−2) or refers to a diagnosis made by a caregiver (e.g.physician, nurse, nurse practitioner in the case of humans; veterinarianin the case of non-human vertebrates).

Osteoporosis can be classified as either primary or secondary. (See,e.g., World Health Organization Technical Report Series 921 (2003),Prevention and Management of Osteoporosis.) As used herein, the term“osteoporosis” encompasses primary osteoporosis and secondaryosteoporosis. In certain embodiments, osteoporosis is primaryosteoporosis. In certain embodiments, osteoporosis is secondaryosteoporosis.

“Primary osteoporosis” as used herein is associated with menopause(natural, premature, or surgical), aging, or both. It shall beunderstood that in the present invention, primary osteoporosisassociated with menopause (natural, premature, or surgical), primaryosteoporosis associated with aging, and primary osteoporosis associatedwith menopause and aging can be included in embodiments individually orin any combination.

“Secondary osteoporosis” as used herein refers to osteoporosis which isassociated not with menopause or aging but rather with medicalconditions or with the use of medications or drugs. An increased risk ofosteoporosis is associated with a host of medical conditions, includingbut not limited to endocrine and metabolic disorders, and malignantdisease, and with the use of certain medications and drugs, examples ofwhich are well known to those skilled in the art (see, e.g., WorldHealth Organization Technical Report Series 921 (2003), Prevention andManagement of Osteoporosis; Williams Textbook of Endocrinology, 10^(th)Edition; the disclosure of which is herein incorporated by reference inits entirety.) Secondary osteoporosis can also be associated withimmobilization. A diagnosis of osteoporosis secondary to a medicalcondition, to use of a medication or drug, or to immobilization can bemade by a caregiver (e.g. physician, nurse, nurse practitioner in thecase of humans; veterinarian in the case of non-human vertebrates).

By “bone fracture” is intended a complete or incomplete break, ruptureor crack of a bone. Diagnosis of fractures normally depends uponclinical examination and radiological findings. In the invention, bonefractures include, but are not limited to, traumatic fractures,long-term fractures, and pathological fractures.

“Traumatic fracture” as used herein shall refer to an immediate fracturewhich involves a supraliminal trauma with a degree of local violencethat exceeds the natural elasticity of the bone. It can be accompaniedby simultaneous injury to the soft tissues and very often the skin. Atraumatic fracture can be closed (the adjacent soft tissue can beinjured but the covering soft parts are largely preserved). A traumaticfracture can be open (the broken ends of the bone are freed by extensivesoft tissue injury so that pathogens from outside can enter the wounddirectly).

“Long-term fracture” as used herein shall refer to a chronic fracture,fatigue fracture, stress fracture or spontaneous fracture type I.

“Pathological fracture” as used herein shall refer to a spontaneousfracture type II. A pathological fracture arises spontaneously, withoutadequate trauma to account for it. The bone may have been previouslydamaged, either by a systemic disease (e.g., osteoporosis,osteodystrophy, or Paget's osteitis deformans) or by a local bone lesion(e.g., metastasis, radioosteonecrosis, or bone tumor). See, Adler,Claus-Peter, BONE DISEASES, p. 114 (Springer-Verlag, Germany 2000).

Fractures also include, but are not limited no, oblique torsionfracture, transverse fracture, comminuted fracture, compressionfracture, rib fractures, creeping fracture, and fractured femoral neck(Adler, Claus-Peter, BONE DISEASES, Springer-Verlag. Germany (2000)).

As used herein, the term “condition characterized by low bone mass”includes but is not limited to osteopenia, osteoporosis, primaryosteoporosis, secondary osteoporosis, rheumatoid arthritis,osteoarthritis, periodontal disease, alveolar bone loss, osteotomy boneloss, childhood idiopathic bone loss, curvature of the spine and loss ofheight. In certain embodiments, secondary osteoporosis is associatedwith a medical condition. In certain embodiments, secondary osteoporosisis associated with use of a medication or drug. In certain embodiments,secondary osteoporosis is associated with immobilization. Conditionscharacterized by low bone mass include but are not limited to Paget'sdisease, bone loss due to metastatic cancer, and osteolytic lesions suchas those caused by neoplastic disease, radiotherapy, or chemotherapy.Conditions characterized by low bone mass also include but are notlimited to long-term complications of osteoporosis such as curvature ofthe spine, loss of height and prosthetic surgery. It shall be understoodthat in the present invention, conditions characterized by low bone masscan be included in embodiments individually or in any combination. (See,e.g., World Health Organization Technical Report Series 921 (2003),Prevention and Management of Osteoporosis; Williams Textbook ofEndocrinology, 10^(th) Edition, Larsen et al, Eds. (2002), W.B. SaundersCompany; and Endocrinology and Metabolism, 4^(th) Edition, Felig et al,Eds. (2001), McGraw-Hill Book Company; the disclosure of each of whichis herein incorporated by reference in its entirety.)

As used herein, “bone disease” refers to a disorder or conditionrelating to abnormality of the bone. Bone diseases that can be treatedaccording to the invention, by increasing bone mass or bone growth,include but are not limited to osteopenia, osteoporosis, primaryosteoporosis, secondary osteoporosis, rheumatoid arthritis,osteoarthritis, periodontal disease, alveolar bone loss, osteotomy boneloss, childhood idiopathic bone loss, curvature of the spine, and lossof height. In certain embodiments, secondary osteoporosis is associatedwith a medical conditions. In certain embodiments, secondaryosteoporosis is associated with the use of a medication or drug. Incertain embodiments, secondary osteoporosis is associated withimmobilization. Bone diseases that can be treated according to theinvention, by increasing bone mass or bone growth, also include but arenot limited to Paget's disease and bone loss due to metastatic cancer.Destructive bone disorders that can be treated according to theinvention, by increasing bone mass or growth, include but are notlimited to osteoporosis, osteoarthritis, and osteolytic lesions such asthose caused by neoplastic disease, radiotherapy, or chemotherapy. Itshall be understood that in the present invention, bone diseases thatcan be treated according to the invention, by increasing bone mass orgrowth, can be included in embodiments individually or in anycombination: (See, e.g., World Health Organization Technical ReportSeries 921 (2003), Prevention and Management of Osteoporosis; WilliamsTextbook of Endocrinology, 10^(th) Edition, Larsen et al, Eds. (2002),W.B. Saunders Company; and Endocrinology and Metabolism, 4^(th) Edition,Felig et at, Eds. (2001), McGraw-Hill Book Company; the disclosure ofeach of which is herein incorporated by reference in its entirety.)

The present invention also relates to the other conditions that derivebenefit from treatment according to the invention, by increasing bonemass or bone growth, including but not limited to enhanced bone healingfollowing facial reconstruction, maxillary reconstruction, mandibularreconstruction, periodontal disease or tooth extraction, enhanced longbone extension, enhanced prosthetic ingrowth and increased bonesynostosis.

Chemical Group, Moiety or Radical

The term “C₁₋₅ acyl” denotes a C₁₋₅ alkyl radical attached to a carbonylwherein the definition of alkyl has the same definition as describedherein; some examples include but not limited to, acetyl, propionyl,n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (i.e., pivaloyl),pentanoyl and the like.

The term “C₁₋₅ acyloxy” denotes an acyl radical attached to an oxygenatom wherein acyl has the same definition has described herein; someexamples include but not limited to acetyloxy, propionyloxy,butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and thelike.

The term “C₁₋₆ acylsulfonamide” refers to a C₁₋₆ acyl attached directlyto the nitrogen of the sulfonamide, wherein the definitions for C₁₋₆acyl and sulfonamide have the same meaning as described herein, and aC₁₋₆ acylsulfonamide can be represented by the following formula:

Some embodiments of the present invention are when acylsulfonamide is aC₁₋₅ acylsulfonamide, some embodiments are C₁₋₄ acylsulfonamide, someembodiments are C₁₋₃ acylsulfonamide, and some embodiments are C₁₋₂acylsulfonamide. Examples of an acylsulfonamide include, but not limitedto, acetylsulfamoyl [—S(═O)₂NHC(═O)Me], propionylsulfamoyl[—S(═O)₂NHC(═O)Et], isobutyrylsulfamoyl, butyrylsulfamoyl,2-methyl-butyrylsulfamoyl, 3-methyl-butyrylsulfamoyl,2,2-dimethyl-propionylsulfamoyl, pentanoylsulfamoyl,2-methyl-pentanoylsulfamoyl, 3-methyl-pentanoylsulfamoyl,4-methyl-pentanoylsulfamoyl, and the like.

The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6 carbonswherein at least one carbon-carbon double bond is present, someembodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, andsome embodiments have 2 carbons. Both E and Z isomers are embraced bythe term “alkenyl.” Furthermore, the term “alkenyl” includes di- andtri-alkenyls. Accordingly, if more than one double bond is present thenthe bonds may be all E or Z or a mixtures of E and Z. Examples of analkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2,4-hexadienyl and the like.

The term “C₁₋₄ alkoxy” as used herein denotes a radical alkyl, asdefined herein, attached directly to an oxygen atom. Examples includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy,sec-butoxy and the like.

The term “C₁₋₈ alkyl” denotes a straight or branched carbon radicalcontaining 1 to 8 carbons, some embodiments are 1 to 6 carbons, someembodiments are 1 to 3 carbons, and some embodiments are 1 or 2 carbons.Examples of an alkyl include, but not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl,iso-pentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “C₁₋₄ alkylcarboxamido” or “C₁₋₄ alkylcarboxamide” denotes asingle C₁₋₄ alkyl group attached to the nitrogen of an amide group,wherein alkyl has the same definition as found herein. The C₁₋₅alkylcarboxamido may be represented by the following:

Examples include, but not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “C₁₋₃ alkylene” refers to a C₁₋₃ divalent straight carbongroup. In some embodiments C₁₋₃ alkylene refers to, for example, —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, and the like. In some embodiments, C₁₋₃ alkylenerefers to —CH—, —CHCH₂—, —CHCH₂CH₂—, and the like wherein these examplesrelate generally to “A”.

The term “C₁₋₄ alkylsulfinyl” denotes a C₁₋₄ alkyl radical attached to asulfoxide radical of the formula: —S(O)— wherein the alkyl radical hasthe same definition as described herein. Examples include, but notlimited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl,iso-butylsulfinyl, t-butyl, and the like.

The term “C₁₋₄ alkylsulfonamide” refers to the groups

-   -   wherein C₁₋₄ alkyl has the same definition as described herein.

The term “C₁₋₄ alkylsulfonyl” denotes a C₁₋₄ alkyl radical attached to asulfone radical of the formula: —S(O)₂— wherein the alkyl radical hasthe same definition as described herein. Examples include, but notlimited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, t-butyl, and the like.

The term “C₁₋₄ alkylthio” denotes a C₁₋₄ alkyl radical attached to asulfide of the formula: —S— wherein the alkyl radical has the samedefinition as described herein. Examples include, but not limited to,methylsulfanyl (i.e., CH₃S—), ethylsulfanyl, n-propylsulfanyl,iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,iso-butylsulfanyl, t-butyl, and the like.

The term “C₁₋₄ alkylthiocarboxamide” denotes a thioamide of thefollowing formulae:

wherein C₁₋₄ alkyl has the same definition as described herein.

The term “C₁₋₄ alkylthioureyl” denotes the group of the formula:—NC(S)N— wherein one are both of the nitrogens are substituted with thesame or different C₁₋₄ alkyl groups and alkyl has the same definition asdescribed herein. Examples of an alkylthioureyl include, but not limitedto, CH₃NHC(S)NH—, NH₂C(S)NCH₃—, (CH₃)₂N(S)NH—, (CH₃)₂N(S)NH—,(CH₃)₂N(S)NCH₃—, CH₃CH₂NHC(S)NH—, CH₃CH₂NHC(S)NCH₃—, and the like.

The term “C₁₋₄ alkylureyl” denotes the group of the formula: —NC(O)N—wherein one are both of the nitrogens are substituted with the same ordifferent C₁₋₄ alkyl group wherein alkyl has the same definition asdescribed herein. Examples of an alkylureyl include, but not limited to,CH₃NHC(O)NH—, NH₂C(O)NCH₃—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NH—,(CH₃)₂N(O)NCH₃—, CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “C₂₋₆ alkynyl” denotes a radical containing 2 to 6 carbons andat least one carbon-carbon triple bond, some embodiments are 2 to 4carbons, some embodiments are 2 to 3 carbons, and some embodiments have2 carbons. Examples of an alkynyl include, but not limited to, ethynyl,1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl,2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl,4-hexynyl, 5-hexynyl and the like. The term “alkynyl” includes di- andtri-ynes.

The term “amino” denotes the group —NH₂.

The term “C₁₋₄ alkylamino” denotes one alkyl radical attached to anamino radical wherein the alkyl radical has the same meaning asdescribed herein. Some examples include, but not limited to,methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino,sec-butylamino, iso-butylamino, t-butylamino, and the like. Someembodiments are “C₁₋₂ alkylamino.”

The term “aryl” denotes an aromatic ring radical containing 6 to 10 ringcarbons. Examples include phenyl and naphthyl.

The term “arylalkyl” defines a C₁-C₄ alkylene, such as —CH₂—, —CH₂CH₂—and the like, which is further substituted with an aryl group. Examplesof an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes a single aryl group attached to thenitrogen of an amide group, wherein aryl has the same definition asfound herein. The example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “carbo-C₁₋₆-alkoxy” refers to a C₁₋₆ alkyl ester of acarboxylic acid, wherein the alkyl group is as defined herein. In someembodiments, the carbo-C₁₋₆-alkoxy group is bonded to a nitrogen atomand together form a carbamate group (e.g., N—COO—C₁₋₆-alkyl). In someembodiments, the carbo-C₁₋₆-alkoxy group is an ester (e.g.,—COO—C₁₋₆-alkyl). Examples include, but not limited to, carbomethoxy,carboethoxy, carbopropoxy, carboisopropoxy, carbobutoxy,carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy,carbo-iso-pentoxy, carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy,and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “C₃₋₇ cycloalkenyl” denotes a non-aromatic ring radicalcontaining 3 to 6 ring carbons and at least one double bond; someembodiments contain 3 to 5 carbons; some embodiments contain 3 to 4carbons. Examples include cyclopropenyl, cyclobutenyl, cyclopentenyl,cyclopentenyl, cyclohexenyl, and the like.

The term “C₃₋₇ cycloalkyl” denotes a saturated ring radical containing 3to 6 carbons; some embodiments contain 3 to 5 carbons; some embodimentscontain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.

The term “C₄₋₈ diacylamino” denotes an amino group bonded with two acylgroups defined herein wherein the acyl groups may be the same ordifferent, such as:

Examples of C₄₋₈ diacylamino groups include, but limited to,diacetylamino, dipropionylamino, acetylpropionylamino and the like.

The term “C₂₋₆ dialkylamino” denotes an amino substituted with two ofthe same or different alkyl radicals wherein alkyl radical has the samedefinition as described herein. Some examples include, but not limitedto, dimethylamino, methylethylamino, diethylamino, methylpropylamino,methylisopropylamino, ethylpropylamino, ethylisopropylamino,dipropylamino, propylisopropylamino and the like. Some embodiments are“C₂₋₄ dialkylamino.”

The term “C₁₋₄ dialkylcarboxamido” or “C₁₋₄ dialkylcarboxamide” denotestwo alkyl radicals, that are the same or different, attached to an amidegroup, wherein alkyl has the same definition as described herein. A C₁₋₄dialkylcarboxamido may be represented by the following groups:

wherein C₁₋₄ has the same definition as described herein. Examples of adialkylcarboxamide include, but not limited to, N,N-dimethylcarboxamide,N-methyl-N-ethylcarboxamide, N,N-diethylcarboxamide,N-methyl-N-isopropylcarboxamide, and the like.

The term “C₂₋₆ dialkylsulfonamide” refers to one of the following groupsshown below:

wherein C₁₋₃ has the same definition as described herein, for examplebut not limited to, methyl, ethyl, n-propyl, isopropyl, and the like.

The term “C₂₋₆ dialkylthiocarboxamido” or “C₂₋₆ dialkylthiocarboxamide”denotes two alkyl radicals, that are the same or different, attached toa thioamide group, wherein alkyl has the same definition as describedherein. A C₁₋₄ dialkylthiocarboxamido may be represented by thefollowing groups:

-   -   Examples of a dialkylthiocarboxamide include, but not limited        to, N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide        and the like.

The term “C₂₋₆ dialkylsulfonylamino” refers to an amino group bondedwith two C₁₋₃ alkylsulfonyl groups as defined herein.

The term “ethynylene” refers to the carbon-carbon triple bond group asrepresented below:

The term “formyl” refers to the group —CHO.

The term “C₁₋₄ haloalkoxy” denotes a haloalkyl, as defined herein, whichis directly attached to an oxygen atom. Examples include, but notlimited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy,pentafluoroethoxy and the like.

The term “C₁₋₄ haloalkyl” denotes an C₁₋₄ alkyl group, defined herein,wherein the alkyl is substituted with one halogen up to fullysubstituted and a fully substituted C₁₋₄ haloalkyl can be represented bythe formula C_(n)L_(2n+1) wherein L is a halogen and “n” is 1, 2, 3 or4; when more than one halogen is present then they may be the same ordifferent and selected from the group consisting of F, Cl, Br and I, inparticular embodiment F. Examples of C₁₋₄ haloalkyl groups include, butnot limited to, fluoromethyl, difluoromethyl, trifluoromethyl,chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and thelike.

The term “C₁₋₄ haloalkylcarboxamide” denotes an alkylcarboxamide group,defined herein, wherein the alkyl is substituted with one halogen up tofully substituted represented by the formula C_(n)L_(2n+1), wherein L isa halogen and “n” is 1, 2, 3 or 4. When more than one halogen is presentthey may be the same or different and selected from the group consistingof F, Cl, Br and I, in particular embodiment F.

The term “C₁₋₄ haloalkylsulfinyl” denotes a haloalkyl radical attachedto a sulfoxide group of the formula: —S(O)— wherein the haloalkylradical has the same definition as described herein. Examples include,but not limited to, trifluoromethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like.

The term “C₁₋₄ haloalkylsulfonyl” denotes a haloalkyl radical attachedto a sulfone group of the formula: —S(O)₂— wherein haloalkyl has thesame definition as described herein. Examples include, but not limitedto, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,2,2-difluoroethylsulfonyl and the like.

The term “C₁₋₄ haloalkylthio” denotes a haloalkyl radical directlyattached to a sulfur wherein the haloalkyl has the same meaning asdescribed herein. Examples include, but not limited to,trifluoromethylthio (i.e., CF₃S—), 1,1-difluoroethylthio,2,2,2-trifluoroethylthio and the like.

The term “halogen” or “halo” denotes to a fluoro, chloro, bromo or iodogroup.

The term “C₁₋₂ heteroalkylene” refers to a C₁₋₂ alkylene bonded to aheteroatom selected from O, S, S(O), S(O)₂ and NH. Some representedexamples include, but not limited to, the groups of the followingformulae:

and the like.

The term “heteroaryl” denotes an aromatic ring system that may be asingle ring, two fused rings or three fused rings wherein at least onering carbon is replaced with a heteroatom selected from, but not limitedto, the group consisting of O, S and N wherein the N can be optionallysubstituted with H, C₁₋₄ acyl or C₁₋₄ alkyl. Examples of heteroarylgroups include, but not limited to, pyridyl, benzofuranyl, pyrazinyl,pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole,benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinoxalineand the like. In some embodiments, the heteroaryl atom is O, S, NH,examples include, but not limited to, pyrrole, indole, and the like.

The term “heterocyclic” denotes a non-aromatic carbon ring (i.e.,cycloalkyl or cycloalkenyl as defined herein) wherein one, two or threering carbons are replaced by a heteroatom selected from, but not limitedto, the group consisting of O, S, N, wherein the N can be optionallysubstituted with H, C₁₋₄ acyl or C₁₋₄ alkyl, and ring carbon atomsoptionally substituted with oxo or a thiooxo thus forming a carbonyl orthiocarbonyl group. The heterocyclic group is a 3-, 4-, 5-, 6- or7-membered containing ring. Examples of a heterocyclic group include butnot limited to aziridin-1-yl, aziridin-2-yl, azetidin-1-yl,azetidin-2-yl, azetidin-3-yl, piperidin-1-yl, piperidin-4-yl,morpholin-4-yl, piperazin-1-yl, piperazin-4-yl, pyrrolidin-1-yl,pyrrolidin-3-yl, [1,3]-dioxolan-2-yl and the like.

The term “heterocyclic-carbonyl” denotes a heterocyclic group, asdefined herein, directly bonded to the carbon of a carbonyl group (i.e.,C═O). In some embodiments, a ring nitrogen of the heterocyclic group isbonded to the carbonyl group forming an amide. Examples include, but notlimited to,

and the like.

In some embodiments, a ring carbon is bonded to the carbonyl groupforming a ketone group.

Examples include, but not limited to,

and the like.

The term “heterocyclic-oxy” refers to a heterocyclic group, as definedherein, that is directly bonded to an oxygen atom. Examples include thefollowing:

and the like.

The term “heterocycliccarboxamido” denotes a heterocyclic group, asdefined herein, with a ring nitrogen where the ring nitrogen is bondeddirectly to the carbonyl forming an amide. Examples include, but notlimited to,

and the like.

The term “heterocyclicsulfonyl” denotes a heterocyclic group, as definedherein, with a ring nitrogen where the ring nitrogen is bonded directlyto an SO₂ group forming an sulfonamide. Examples include, but notlimited to,

and the like.

The term “hydroxyl” refers to the group —OH.

The term “hydroxylamino” refers to the group —NHOH.

The term “nitro” refers to the group —NO₂.

The term “C₄₋₇ oxo-cycloalkyl” refers to a C₄₋₇ cycloalkyl, as definedherein, wherein one of the ring carbons is replaced with a carbonyl.Examples of C₄₋₇ oxo-cycloalkyl include, but are not limited to,2-oxo-cyclobutyl, 3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl,and the like and represented by the following structures respectively:

The term “perfluoroalkyl” denotes the group of the formula—C_(n)F_(2n+1); stated differently, a perfluoroalkyl is an alkyl asdefined herein wherein the alkyl is fully substituted with fluorineatoms and is therefore considered a subset of haloalkyl. Examples ofperfluoroalkyls include CF₃, CF₂CF₃, CF₂CF₂CF₃, CF(CF₃)₂, CF₂CF₂CF₂CF₃,CF₂CF(CF₃)₂, CF(CF₃)CF₂CF₃ and the like.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term “phosphonooxy” refers to a group with the following chemicalstructure:

The term “sulfonamide” refers to the group —SO₂NH₂.

The term “sulfonic acid” refers to the group —SO₃H.

The term “tetrazolyl” refers to the five membered heteroaryl of thefollowing formulae:

In some embodiments, the tetrazolyl group is further substituted ateither the 1 or 5 position respectively with a group selected from thegroup consisting of C₁₋₃ alkyl, C₁₋₃ haloalkyl and C₁₋₃ alkoxy.

The term “thiol” denotes the group —SH.

The term “endogenous” shall mean a material that an individual (forexample, and not limitation, a human) naturally produces. By contrast,“non-endogenous” shall mean that which is not naturally produced by anindividual (for example, and not limitation, a human).

The term “host cell” shall mean a cell capable of having a vectorincorporated therein. In the present context, the vector will typicallycontain nucleic acid encoding a GPCR or GPCR fusion protein in operableconnection with a suitable promoter sequence to permit expression of theGPCR or GPCR fusion protein to occur. In particular embodiment, the hostcell is a eukaryotic host cell. In certain embodiments, the eukaryotichost cell is a mammalian host cell. In certain embodiments, theeukaryotic host cell is a yeast host cell. In certain embodiments, theeukaryotic host cell is a melanophore host cell.

The term “contact” or “contacting” shall mean bringing at least twomoieties together.

The terms “modulate” or “modify” shall be taken to refer to an increaseor decrease in the amount, quality, or effect of a particular activity,function or molecule. By way of illustration and not limitation,agonists, partial agonists, inverse agonists, and antagonists of a Gprotein-coupled receptor are modulators of the receptor.

The term “small molecule” shall be taken to mean a compound having amolecular weight of less than about 10,000 grams per mole, including apeptide, peptidomimetic, amino acid, amino acid analogue,polynucleotide, polynucleotide analogue, nucleotide, nucleotideanalogue, organic compound or inorganic compound (i.e. including aheterorganic compound or organometallic compound), and salts, esters andother pharmaceutically acceptable forms thereof. In certain embodiments,small molecules are organic or inorganic compounds having a molecularweight of less than about 5,000 grams per mole. In certain embodiments,small molecules are organic or inorganic compounds having molecularweight of less than about 1,000 grams per mole. In certain embodiments,small molecules are organic or inorganic compounds having a molecularweight of less than about 800 grams per mole. In certain embodiments,small molecules are organic or inorganic compounds having a molecularweight of less than about 600 grams per mole. In certain embodiments,small molecules are organic or inorganic compounds having a molecularweight of less than about 500 grams per mole.

Amino acid abbreviations used herein are set out in Table F:

TABLE F ALANINE ALA A ARGININE ARG R ASPARAGINE ASN N ASPARTIC ACID ASPD CYSTEINE CYS C GLUTAMIC ACID GLU E GLUTAMINE GLN Q GLYCINE GLY GHISTIDINE HIS H ISOLEUCINE ILE I LEUCINE LEU L LYSINE LYS K METHIONINEMET M PHENYLALANINE PHE F PROLINE PRO P SERINE SER S THREONINE THR TTRYPTOPHAN TRP W TYROSINE TYR Y VALINE VAL V

The term “polypeptide” shall refer to a polymer of amino acids withoutregard to the length of the polymer. Thus, peptides, oligopeptides, andproteins are included within the definition of polypeptide. This termalso does not specify or exclude post-expression modifications ofpolypeptides. For example, polypeptides that include the covalentattachment of glycosyl groups, acetyl groups, phosphate groups, lipidgroups and the like are expressly encompassed by the term polypeptide.

The term “antibody” is intended herein to encompass monoclonal antibodyand polyclonal antibody.

The term “second messenger” shall mean an intracellular responseproduced as a result of receptor activation. A second messenger caninclude, for example, inositol 1,4,5-triphosphate (IP₃), diacylglycerol(DAG), cyclic AMP (cAMP), cyclic GMP (cGMP), MAP kinase activity,MAPK/ERK kinase kinase-1 (MEKK1) activity, and Ca²⁺. Second messengerresponse can be measured for a determination of receptor activation.

The term “receptor functionality” shall refer to the normal operation ofa receptor to receive a stimulus and moderate an effect in the cell,including, but not limited to regulating gene transcription, regulatingthe influx or efflux of ions, effecting a catalytic reaction, and/ormodulating activity through G-proteins, such as eliciting a secondmessenger response.

The term “stimulate” or “stimulating,” in relationship to the term“response” or “functionality of the receptor” shall mean that a responseor a functionality of the receptor is increased in the presence of acompound as opposed to in the absence of the compound.

The term “inhibit” or “inhibiting,” in relationship to the term“response” or “functionality of the receptor” shall mean that a responsea functionality of the receptor is decreased or prevented in thepresence of a compound as opposed to in the absence of the compound.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the lower limit unless the contextclearly indicates otherwise, between the upper and lower limit of thatrange and any other stated or intervening value in that stated range, isencompassed within the invention. The upper and lower limits of thesesmaller ranges may independently be included in the smaller ranges, andare also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

GPR119 Agonists

In certain embodiments, GPR119 is mammalian GPR119. In certainembodiments, GPR119 is rodent or primate GPR119. In certain embodiments,GPR119 is human GPR119.

The class of GPR119 agonists useful in compositions and methods of thepresent invention including but not limited to the novel therapeuticcombinations of the present invention include compounds which exhibit anacceptably high affinity for GPR119 receptor. The GPR119 agonist orpharmaceutically acceptable salt may be any agonist, and in particularembodiment a selective GPR119 agonist.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/001267 (published as WO 04/065380), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2004/001267 as a GPR119 agonist is acompound of Formula (I):

wherein:

-   -   A and B are independently C₁₋₃ alkylene optionally substituted        with 1 to 4 methyl groups;    -   D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂;    -   V is selected from the group consisting of C₁₋₃ alkylene,        ethynylene and C₁₋₂ heteroalkylene wherein each are optionally        substituted with 1 to 4 substituents selected from the group        consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃        haloalkyl and halogen; or    -   V is absent;    -   W is NR₄, O, S, S(O) or S(O)₂; or    -   W is absent;    -   X is N or CR₅;    -   Y is N or CR₆;    -   Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₄₋₈        diacylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,        C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl,        heterocyclic, heteroaryl, hydroxyl, hydroxylamino, nitro and        tetrazolyl, wherein C₁₋₈ alkyl and C₁₋₅ acyl are each optionally        substituted with 1, 2, 3 or 4 groups selected from the group        consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄        alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂        alkylamino, C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl,        C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, hydroxyl,        hydroxylamino and nitro; or    -   Z is a group of Formula (IA):

-   -   -   wherein:            -   R₇ is H, C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and            -   R₈ is H, nitro or nitrile;

    -   Ar₁ is aryl or heteroaryl wherein each are optionally        substituted with R₉-R₁₃;

    -   R₁ is selected from the group consisting of H, C₁₋₅ acyloxy,        C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,        C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄        alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₆        cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio        and hydroxyl;

    -   R₂ is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, hydroxyl and        phenyl; and wherein C₁₋₈ alkyl, heteroaryl and phenyl are each        optionally substituted with 1 to 5 substituents selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-alkylene,        C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆        dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,        hydroxylamino and nitro; or

    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are independently aryl or        heteroaryl each optionally substituted with 1 to 5 substituents        selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or

    -   R₂ is a group of Formula (IB):

-   -   -   wherein:            -   R₁₄ is C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₁₅ is F, Cl,                Br or CN; or

    -   R₂ is a group of Formula (IC):

-   -   -   wherein:            -   G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; where R₁₆ and R₁₇                are independently H or C₁₋₈ alkyl; and            -   Ar₄ is phenyl or heteroaryl optionally substituted with                1 to 5 substituents selected from the group consisting                of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,                C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄                alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄                alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄                alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,                carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆                dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₄                dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄                haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄                haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio,                halogen, heteroaryl, hydroxyl, hydroxylamino and nitro;

    -   R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy, halogen or hydroxyl;

    -   R₄ is H or C₁₋₈ alkyl;

    -   R₅ and R₆ are independently H, C₁₋₈ alkyl or halogen;

    -   R₉ is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino,        C₁₋₄ alkylcarboxamide, C₂₋₄ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, arylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylamino, C₂₋₄        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic,        heterocyclicsulfonyl, heteroaryl, hydroxyl, nitro, C₄₋₇        oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic acid,        and wherein C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylsulfonamide, alkylsulfonyl, arylsulfonyl, heteroaryl,        phenoxy and phenyl are each optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₄ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆        cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro        and phenyl; or

    -   R₉ is a group of Formula (ID):

-   -   -   wherein:            -   “p” and “r” are independently 0, 1, 2 or 3; and            -   R₁₈ is H, C₁₋₅ acyl, C₂₋₄ alkenyl, C₁₋₈ alkyl, C₁₋₄                alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,                carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆                cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl                or phenyl, and wherein the heteroaryl and phenyl are                each optionally substituted with 1 to 5 substituents                selected independently from the group consisting of C₁₋₄                alkoxy, amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₆                dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl                and hydroxyl; and

    -   R₁₀-R₁₃ are independently selected form the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆        cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, hydroxyl and nitro; or

    -   two adjacent R₁₀-R₁₁ groups together with Ar₁ form a 5, 6 or 7        membered cycloalkyl, cycloalkenyl or heterocyclic group wherein        the 5, 6 or 7 membered group is optionally substituted with        halogen.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/001267 include the following compoundsaccording to Formula (I) (referred to herein as Group A1):[6-(4-Benzenesulfonyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperazin-1-yl}-aceticacid ethyl ester;(2-Fluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;{6-[4-(4-Fluoro-phenoxy)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;{6-[4-(3-Cyclopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-phenyl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(3-propyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;{6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyrimidin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(4-Carbamoylmethyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;4′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;{6-[4-(2-Methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;4′-(2-Amino-4-ethanesulfonyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;4′-(4-Imidazol-1-yl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;(4-Methoxy-2-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-phenyl-methanone;4-{4-[6-(4-Cyclopropylmethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[5-Nitro-6-(4-propoxymethyl-piperidin-1-yl)-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[6-(4-Butoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;4-{4-[6-(4-Isobutoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yloxy]-phenyl}-butan-2-one;{1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-(4-fluoro-phenyl)-methanone;(2,3-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2,4-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-{2-Nitro-3-[4-(3-oxo-butyl)-phenoxy]-phenyl})-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Acetyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;3′-Nitro-2′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl-4-carboxylicacid ethyl ester;4-(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-{5-Nitro-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(2,4-Difluoro-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine;4-(4-{6-[4-(4-Fluoro-benzoyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yloxy}-phenyl)-butan-2-one;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-2-ylsulfanyl)-cyclohexyl]-pyrimidine;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-[4-(pyridin-4-ylsulfanyl)-cyclohexyl]-pyrimidine;4-(4-Methanesulfonyl-phenoxy)-5-nitro-6-(4-phenylsulfanyl-cyclohexyl)-pyrimidine;1-{6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(1,1-Dioxo-1λ⁶-thiomorpholin-4-ylmethyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Methoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(4-Methanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2,5-Dimethoxy-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;(4-{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-ylamino}-phenyl)-phenyl-methanone;1-[6-(4-Cyclohexyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,4])triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;[6-(4-Ethoxymethyl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;[5-Nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine;{5-Nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(2-Fluoro-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[4-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;{6-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(3-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-[6-(Benzo[1,3]dioxol-5-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3-Fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(3,4-Dihydro-2H-benzo[b][1,4]dioxepin-7-ylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(Morpholine-4-sulfonyl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;Benzo[1,3]dioxol-5-yl-[5-nitro-6-(4-propyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(4-Fluoro-phenyl)-{1-[5-nitro-6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}-methanone;[5-Nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine;(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-phenylsulfanyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(pyridin-4-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[4-(4-methoxy-phenylsulfanyl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine;2-Methoxy-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-(5-nitro-6-{4-[3-(3-trifluoromethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-pyrimidin-4-yl)-amine;{6-[4-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(6-{4-[5-(4-Fluoro-phenyl)-[1,3,4]oxadiazol-2-yl]-piperidin-1-yl}-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(4-pyridin-2-ylmethyl-piperidin-1-yl)-pyrimidin-4-yl]-amine;1-{6-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-propionyl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[5-Nitro-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-[4-(3-Oxo-butyl)-phenoxy]-5-(2,2,2-trifluoro-acetylamino)-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-[6-(2-Benzoyl-5-methoxy-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;3′-Nitro-4′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester; 1-[6-(4-Dimethylsulfamoyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylicacid ethyl ester;1-{6-[4-(4,5-Dichloro-imidazol-1-yl)-phenylamino]-5-nitro-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;Benzo[1,3]dioxol-5-yl-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(4-Fluoro-phenyl)-{1-[6-(2-fluoro-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-methanone;(2,5-Difluoro-phenyl)-{5-nitro-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;1-{5-Nitro-6-[4-(3-oxo-butyl)-phenoxy]-pyrimidin-4-yl}-piperidine-4-carboxylicacid ethyl ester;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbonitrile;5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine-5-carbaldehyde;5-[1,3]Dioxolan-2-yl-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carbaldehyde;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidine-5-carboxylicacid;[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-yl]-methanol;[4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-pyrimidin-5-ylmethyl]-dimethyl-amine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methylsulfanyl-phenylamino)-pyrimidine-5-carbonitrile;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfinyl-phenylamino)-pyrimidine-5-carbonitrile;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[4-(4-trifluoromethoxy-phenoxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile;1-{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one;1-{1-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yl]-piperidin-4-yl}-hexan-1-one;{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;{6-[4-(3-tert-Butyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;[6-(4-Benzofuran-2-yl-piperidin-1-yl)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amineand5-Nitro-4-(5-phenyl-[1,3,4]oxadiazol-2-ylsulfanyl)-6-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-pyrimidine.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/005555 (published as WO 04/076413), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2004/005555 as a GPR119 agonist is acompound of Formula (II):

wherein:

-   -   A and B are independently C₁₋₃ alkylene optionally substituted        with 1 to 4 methyl groups;    -   U is N or CR₁;    -   D is O, S, S(O), S(O)₂, CR₂R₃ or NR₂;    -   V is selected from the group consisting of C₁₋₃ alkylene,        ethynylene and C₁₋₂ heteroalkylene optionally substituted with 1        to 4 substituents selected from the group consisting of C₁₋₃        alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;        or V is absent;    -   W is —S(O)₂NR₄—, —NR₄—, —O—, —S—, —S(O)—, —S(O)₂—; or W is        absent;    -   X is N or CR₅;    -   Y is N or CR₆;    -   Z is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₄₋₈ diacylamino, C₁₋₄ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,        C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl,        heteroaryl, hydroxyl, hydroxylamino, nitro and tetrazolyl; or    -   Z is a group of Formula (IIA):

-   -   -   wherein:            -   R₇ is H, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and            -   R₈ is H, nitro or cyano;

    -   Ar₁ is aryl or heteroaryl optionally substituted with R₉, R₁₀,        R₁₁, R₁₂ and R₁₃;

    -   R₁, R₅ and R₆ are independently selected from the group        consisting of H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈        dialkylamino, carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl and nitro;

    -   R₂ is selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl, hydroxyl and        phenyl; and wherein C₁₋₈ alkyl, heteroaryl and phenyl are        optionally substituted with 1 to 5 substituents selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxy)amino        and nitro; or

    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are independently aryl or        heteroaryl optionally substituted with 1 to 5 substituents        selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₂₋₆ dialkylcarboxamide, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or

    -   R₂ is a group of Formula (IIB):

-   -   -   wherein:            -   R₁₄ is C₁₋₈ alkyl or C₃₋₆ cycloalkyl; and R₁₅ is F, Cl,                Br or CN; or R₂ is a group of Formula (IIC):

-   -   -   wherein:            -   G is C═O, CR₁₆R₁₇, O, S, S(O), S(O)₂; where R₁₆ and R₁₇                are independently H or C₁₋₈ alkyl; and            -   Ar₄ is phenyl or heteroaryl optionally substituted with                1 to 5 substituents selected from the group consisting                of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,                C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄                alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄                alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄                alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,                carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₆                dialkylcarboxamide, C₁₋₄ dialkylthiocarboxamide, C₂₋₆                dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄                haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄                haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio,                halogen, heteroaryl, hydroxyl, hydroxylamino and nitro;

    -   R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy or hydroxyl;

    -   R₄ is H or C₁₋₈ alkyl;

    -   R₉ is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, arylsulfonyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl, nitro,        C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide and sulfonic        acid, and wherein C₁₋₅ acyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylsulfonamide, alkylsulfonyl, arylsulfonyl, heteroaryl,        phenoxy and phenyl are optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆        cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro        and phenyl; or

    -   R₉ is a group of Formula (IID):

-   -   -   wherein:            -   “p” and “r” are independently 0, 1, 2 or 3; and            -   R₁₈ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄                alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,                carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆                cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl                or phenyl, and wherein the heteroaryl or phenyl                optionally substituted with 1 to 5 substituents selected                independently from the group consisting of C₁₋₄ alkoxy,                C₁₋₈ alkyl, amino, C₁₋₄ alkylamino, C₂₋₄ alkynyl, C₂₋₈                dialkylamino, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl                and hydroxyl; and

    -   R₁₀-R₁₃ are independently selected form the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl and nitro; or

    -   two adjacent R₁₀R₁₁ groups form a 5, 6 or 7 membered cycloalkyl,        cycloalkenyl or heterocyclic group with Ar₁ wherein the 5, 6 or        7 membered group is optionally substituted with halogen.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B1):6′-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;1-[4-(4-Acetyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy)-phenyl]-ethanone;6′-[4-(4-Hydroxy-benzenesulfonyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Imidazol-1-yl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Benzoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-[4-(2-Methoxy-ethyl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Cyclopentyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4′-Cyano-biphenyl-4-yloxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-sulfo-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-pyrrol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4-Carbamoyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(2-Amino-4-ethanesulfonyl-phenoxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-[4-(4-oxo-cyclohexyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(4′-Methoxy-biphenyl-4-yloxy)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-(4-[1,2,3]thiadiazol-4-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-[4-(2,5-Dioxo-imidazolidin-4-yl)-phenoxy]-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3′-Nitro-6′-[4-(3-oxo-butyl)-phenoxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;3-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy)-phenyl]-3-oxo-propionicacid methyl ester;4-[4-(3′-Nitro-4-propyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy)-phenyl]-butan-2-one;4-{4-[3′-Nitro-4-(pyridin-2-ylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yloxy}-phenyl]-butan-2-one;and3′-Nitro-4-(pyridin-2-ylsulfanyl)-6′-(4-[1,2,4]triazol-1-yl-phenoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B2):1-[5-(4-Benzoyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylic acidethyl ester;1-{5-[4-(2-Methoxycarbonyl-acetyl)-phenoxy]-2-nitro-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-[5-(2-Amino-4-ethanesulfonyl-phenoxy)-2-nitro-phenyl]-piperidine-4-carboxylicacid ethyl ester;1-{2-Nitro-5-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylicacid ethyl ester;4-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone;3-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-3-oxo-propionicacid methyl ester;5-Ethanesulfonyl-2-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenylamine;{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone;1-{4-Nitro-3-[4-(3-oxo-butyl)-phenoxy]-phenyl}-piperidine-4-carboxylicacid ethyl ester;4-{4-[2-Nitro-5-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-2-one;1-[3-(4-Benzoyl-phenoxy)-4-nitro-phenyl]-piperidine-4-carboxylic acidethyl ester;{4-[2-Nitro-5-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-phenyl-methanone;1-{5-[4-(2-Carboxy-ethyl)-phenoxy]-2-nitro-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-{5-[4-(2-Carboxy-2-oxo-ethyl)-phenoxy]-2-nitro-phenyl}-piperidine-4-carboxylicacid ethyl ester;1-[2-Nitro-5-(4-vinyl-phenoxy)-phenyl]-piperidine-4-carboxylic acidethyl ester;3-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-propionicacid;3-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-2-oxo-propionicacid; 1-[2-Nitro-5-(4-vinyl-phenoxy)-phenyl]-4-propyl-piperidine;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-butan-1-one;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-pentan-1-one;1-{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-hexan-1-one;4-{4-[3-(4-Methoxymethyl-piperidin-1-yl)-4-nitro-phenoxy]-phenyl}-butan-2-one;1-{4-[3-(4-Methoxymethyl-piperidin-1-yl)-4-nitro-phenoxy]-phenyl}-ethanone;{4-[3-(4-Methoxymethyl-piperidin-1-yl)-4-nitro-phenoxy]-phenyl}-phenyl-methanone;2-(3-Methyl-[1,2,4]oxadiazol-5-yl)-1-{4-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-ethanone;4-(4-{3-[4-(3-Methyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-4-nitro-phenoxy}-phenyl)-butan-2-one;4-(4-{4-Nitro-3-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-phenoxy}-phenyl)-butan-2-one;2-{1-[2-Nitro-5-(4-[1,2,4]triazol-1-yl-phenoxy)-phenyl]-piperidin-4-ylsulfanyl}-pyridine;2-Methyl-5-{4-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-phenyl}-2H-pyrazol-3-ol;2-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-5-trifluoromethyl-pyridine;5-Bromo-2-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenoxy]-pyridine;1-(4-{4-Nitro-3-[4-(pyridin-2-ylsulfanyl)-piperidin-1-yl]-phenoxy}-phenyl)-ethanone;2-{1-[5-(4-Methanesulfonyl-phenoxy)-2-nitro-phenyl]-piperidin-4-ylsulfanyl}-pyridine;1-{5-[4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-phenoxy]-2-nitro-phenyl}-4-propyl-piperidine;1-{5-[3-(3-Methyl-[1,2,4]oxadiazol-5-yl)-phenoxy]-2-nitro-phenyl}-4-propyl-piperidine.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundaccording to Formula (II) (referred to herein as Group B3):5-Bromo-1-[4-nitro-3-(4-propyl-piperidin-1-yl)-phenyl]-1H-pyridin-2-one.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B4):6′-Benzenesulfonylamino-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(Benzenesulfonyl-methyl-amino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(Benzenesulfonyl-butyl-amino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(5-Ethanesulfonyl-2-hydroxy-phenylamino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;6′-(2-Bromo-4-trifluoromethyl-benzenesulfonylamino)-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylicacid ethyl ester;{4-[3′-Nitro-4-(pyridin-2-ylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-ylamino]-phenyl}-phenyl-methanoneand[3′-Nitro-4-(pyridin-2-ylsulfanyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-(4-[1,2,4]triazol-1-yl-phenyl)-amine.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/005555 include the following compoundsaccording to Formula (II) (referred to herein as Group B5):1-[5-(4-Benzoyl-phenylamino)-2-nitro-phenyl]-piperidine-4-carboxylicacid ethyl ester and{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)-phenylamino]-phenyl}-phenyl-methanone.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/022327 (published as WO 05/007647), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2004/022327 as a GPR119 agonist is acompound of Formula (II):

-   -   wherein:    -   A and B are each independently C₁₋₃ alkylene optionally        substituted with 1 to 4 substituents selected from the group        consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃        haloalkyl and halogen;    -   D is O, S, S(O), S(O)₂, CR₂R₃ or N—R₂;    -   E is N, C or CR₄;    -   is a single bond when E is N or CR₄, or a double bond when E is        C;    -   V₁ is selected from the group consisting of C₁₋₃ alkylene,        ethynylene and C₁₋₂ heteroalkylene optionally substituted with 1        to 4 substituents selected from the group consisting of C₁₋₃        alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl and halogen;        or V₁ is a bond;    -   V₂ is C₃₋₆ cycloalkylene or C₁₋₃ alkylene wherein each are        optionally substituted with 1 to 4 substituents selected from        the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano,        C₁₋₃ haloalkyl and halogen; or V₂ is a bond;    -   W is NR₅, O, S, S(O) or S(O)₂; or W is absent;    -   Q is NR₆, O, S, S(O) or S(O)₂;    -   X is N or CR₇;    -   Y is N or CR₈;    -   Z is selected from the group consisting of C₁₋₅ acyl, C₁₋₅        acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄        alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylthiocarboxamide, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, C₁₋₂        alkylamino, C₂₋₄ dialkylamino, carbamimidoyl, carbo-C₁₋₆-alkoxy,        carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₄₋₈ diacylamino,        C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        halogen, aryl, heterocyclic, heteroaryl, hydroxyl,        hydroxycarbamimidoyl, hydroxylamino, nitro and tetrazolyl,        wherein C₁₋₈ alkyl, C₃₋₇ cycloalkyl, and heterocyclic are each        optionally substituted with 1, 2, 3 or 4 groups selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄        alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄        alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, formyl, C₁₋₄        haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro, and        wherein said C₁₋₇ alkyl is optionally substituted with amino; or    -   Z is a group of Formula (IIIA):

-   -   wherein:    -   R₉ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl; and    -   R₁₀ is H, nitro or nitrile;    -   Ar₁ is aryl or heteroaryl each optionally substituted with R₁₁,        R₁₂, R₁₃, R₁₄, and R₁₅; wherein R₁₁ is selected from the group        consisting of C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy,        C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        arylsulfonyl, carbamimidoyl, carbo-C₁₋₆ alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,        heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,        heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl,        phenoxy, phenyl, sulfonamide, sulfonic acid, and thiol, and        wherein C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylsulfonamide, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆        dialkylamino, heterocyclic, heterocyclic-carbonyl, heteroaryl,        phenoxy and phenyl are optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl,        C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro,        phenyl, and phosphonooxy, wherein said C₁₋₇ alkyl and C₁₋₄        alkylcarboxamide are each optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₄ alkoxy        and hydroxy; or    -   R₁₁ is a group of Formula (IIIB):

-   -   wherein:    -   “p” and “r” are each independently 0, 1, 2 or 3; and R₁₆ is H,        C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆        alkynyl, C₁₋₄ alkylsulfonamide, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, heteroaryl or phenyl, and wherein the heteroaryl or        phenyl optionally substituted with 1 to 5 substituents selected        independently from the group consisting of C₁₋₄ alkoxy, amino,        C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl and hydroxyl; and    -   R₁₂, R₁₃, R₁₄, and R₁₅ are each independently selected form the        group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄        alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        hydroxyl and nitro; or    -   two adjacent groups selected from the group consisting of R₁₂,        R₁₃, R₁₄ and R₁₅ together with the atoms to which they are        attached form a 5-, 6- or 7-membered cycloalkyl, cycloalkenyl or        heterocyclic group fused with Ar₁, wherein the 5-, 6- or        7-membered group is optionally substituted with halogen;    -   R₁, R₇ and R₈ are each independently selected from the group        consisting of H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈        dialkylamino, carboxamide, cyano, C₃₋₇ cycloalkyl, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio and hydroxyl;    -   R₂ is selected from the group consisting of C₁₋₈ alkyl, amino,        aryl, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, halogen, heteroaryl and hydroxyl;        and wherein C₁₋₈ alkyl, aryl or heteroaryl optionally        substituted with 1 to 5 substituents selected from the group        consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl,        C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₆-cycloalkyl, C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heterocyclic, hydroxyl, hydroxylamino        and nitro; or    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are each independently aryl        or heteroaryl optionally substituted with 1 to 5 substituents        selected from the group consisting of H, C₁₋₅ acyl, C₁₋₅        acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, amino, C₁₋₄ alkylamino, carbo-C₁₋₆-alkoxy,        carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl, C₂₋₈ dialkylamino,        C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl,        halogen, hydroxyl and nitro; or    -   R₂ is a group of Formula (IIIC):

-   -   wherein:    -   R₁₇ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl or OR₁₉;        and R₁₈ is F, Cl, Br, CN or NR₂₀R₂₁; where R₁₉ is H, C₁₋₈ alkyl        or C₃₋₇ cycloalkyl, and R₂₀ and R₂₁ are each independently H,        C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl or heteroaryl; or    -   R₂ is a group of Formula (IIID):

-   -   wherein:    -   G is:    -   i) —C(O)—, —C(O)NR₂₃—, —C(O)O—, —OC(O)NR₂₃—, —NR₂₃C(O)O—,        —OC(O)—, —C(S)—, —C(S)NR₂₃—, —C(S)O—, —OC(S)—, —CR₂₃R₂₄—, —O—,        —S—, —S(O)— or —S(O)₂— when D is CR₂R₃, or    -   ii) —CR₂₃R₂₄C(O)—, —C(O)—, —CR₂₃R₂₄C(O)NR₂₅—, —C(O)NR₂₃—,        —C(O)O—, —C(S)—, —C(S)NR₂₃—, —C(S)O—, —CR₂₃R₂₄—, —S(O)₂—, or a        bond when D is NR₂,    -   wherein R₂₃, R₂₄ and R₂₅ are each independently H or C₁₋₈ alkyl;        and R₂₂ is H, C₁₋₈ alkyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, phenyl,        heteroaryl, or heterocyclic each optionally substituted with 1        to 5 substituents selected from the group consisting of C₁₋₅        acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄        alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, heteroaryl, heterocyclic, hydroxyl,        hydroxylamino, nitro, phenyl, phenoxy, and sulfonic acid,        wherein said C₁₋₇ alkyl, heteroaryl, phenyl and phenoxy are each        optionally substituted with 1 to 5 substituents selected from        the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy,        C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄        alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,        C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄        alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,        cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,        hydroxylamino, and nitro;    -   R₃ is H, C₁₋₈ alkyl, C₁₋₄ alkoxy or hydroxyl; and    -   R₄, R₅ and R₆ are each independently H, C₁₋₈ alkyl or C₃₋₇        cycloalkyl, wherein said C₁₋₈ alkyl is optionally substituted        with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C1):3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(6-methylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;[6-(1-Hexyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;[6-(1-Cyclopropylmethyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-(4-methanesulfonyl-phenyl)-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-isopropyl-5-methyl-cyclohexyl ester;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone;(2-Chloro-pyridin-3-yl)-{4-[6-(4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-2-yl-methanone;(4-Methanesulfonyl-phenyl)-[6-(1-methanesulfonyl-piperidin-4-yloxy)-5-nitro-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[1-(propane-1-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;{6-[1-(Butane-1-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{5-nitro-6-[1-(thiophene-2-sulfonyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-{6-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-amine;{6-[1-(2,4-Dimethyl-thiazole-5-sulfonyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-[5-Cyano-6-(3-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methanesulfonyl-pyridin-3-ylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;4-[5-Cyano-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;4-(4-Methanesulfonyl-phenylamino)-6-[1-(tetrahydro-furan-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile;4-[1-(3,3-Dimethyl-2-oxo-butyl)-piperidin-4-yloxy]-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrile;4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-3-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile;4-(1-Formyl-piperidin-4-yloxy)-6-(4-methanesulfonyl-phenylamino)-pyrimidine-5-carbonitrileand4-(4-Methanesulfonyl-phenylamino)-6-[1-(pyridine-2-carbonyl)-piperidin-4-yloxy]-pyrimidine-5-carbonitrile.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C2):4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine:1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-1-one;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-2-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(1-pyridin-3-ylmethyl-piperidin-4-yloxy)-pyrimidin-4-yl]-amine;{6-[1-(3,3-Dimethyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;(4-Methanesulfonyl-phenyl)-{6-[1-(3-methyl-butyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-amine;(4-Methanesulfonyl-phenyl)-[5-nitro-6-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;{6-[1-(2-Ethoxy-ethyl)-piperidin-4-yloxy]-5-nitro-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-piperidine-1-carboxylicacid tert-butyl ester;4-{2-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-ethyl}-piperidine-1-carboxylicacid tert-butyl ester;3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester and3-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C3):4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;N-(4-Methanesulfonyl-phenyl)-5-nitro-N′-piperidin-4-yl-pyrimidine-4,6-diamine;1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-ethanoneand1-{4-[6-(4-Methanesulfonyl-phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-2,2-dimethyl-propan-1-one.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C4):4-[6-(4-Cyano-2-fluoro-phenylamino)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-ylamino}-3-fluoro-benzonitrile;{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;4-{6-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-sulfamoyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylic,acid isopropyl ester;4-{6-[6-(2-Fluoro-ethyl)-2-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[4-Fluoro-6-(2-isopropoxy-ethyl)-pyridin-3-ylamino]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-[1,2,4]triazol-1-yl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[2-fluoro-4-(4-methoxy-pyridin-2-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-propionylsulfamoyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-{6-[2,3-Difluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C5):4-[5-Acetyl-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;1-[4-(1-Benzyl-azetidin-3-yloxy)-6-(6-methanesulfonyl-pyridin-3-ylamino)-pyrimidin-5-yl]-ethanone;4-[5-Cyano-6-(6-propylamino-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-isopropylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(6-propyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethylsulfanyl)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethanesulfonyl)-2-fluoro-phenylamino]-3-oxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(3-methyl-butylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-morpholin-4-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[4-(2-dimethylamino-ethylamino)-2-fluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(4-dimethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(2-pyrrolidin-1-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyano-6-[2-fluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-iodo-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyano-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propylamino-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methoxy-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethylamino)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(2-methanesulfonyl-ethyl)-methyl-amino]-phenylamino}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-morpholin-4-yl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-2-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(2-methyl-6-morpholin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-(4,5-Dihydro-1H-imidazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidin-4-yl}-amine;4-[6-(2-Fluoro-4-propoxy-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-(N-hydroxycarbamimidoyl)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Carbamimidoyl-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(4-methyl-6-morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethoxy)-4-methyl-pyridin-3-ylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-methoxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylsulfamoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(N-hydroxycarbamimidoyl)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[(2-Fluoro-4-methanesulfonyl-phenyl)-(2-methoxy-ethyl)-amino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamimidoyl-2,5-difluoro-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Ethoxy-ethoxy)-2-fluoro-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-pyran-4-yloxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;4-{6-[2-Fluoro-4-(pyridin-2-ylmethoxy)-phenylamino]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-3-methyl-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Chloro-4-fluoro-pyridin-3-ylamino)-5-cyano-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-[5-Amino-6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundaccording to Formula (III) (referred to herein as Group C6):4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C7):4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-methoxy-propyl)-piperidin-4-yloxy]-5-methyl-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-2-ol;4-{6-[2-Fluoro-4-(5-isopropoxymethyl-[1,2,4]oxadiazol-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(5-methoxy-pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Cyclopropoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(pyridine-2-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methanesulfonylamino-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methoxy-6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)-propan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-(4-trifluoromethoxy-phenoxy)-ethanone;N-(4-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;N-(3-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;N-(3,5-Dichloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-trifluoromethyl-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-phenyl-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-isopropyl-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(4-methoxy-phenyl)-acetamide;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-N-(3-trifluoromethyl-phenyl)-acetamide;4-{6-[2-Fluoro-4-(3-methoxy-propane-1-sulfonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methyl-6-[2-methyl-6-(2-pyridin-2-yl-ethoxy)-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(thiophene-2-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{6-[(2-Isopropoxy-ethyl)-methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Amino-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(3-methyl-butyl)-piperidin-4-yloxy]-pyrimidine;2-({4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-morpholin-4-yl-ethanone;1-(3,4-Dichloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(3-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-3-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-phenyl-ethanone;1-(2,4-Dimethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(4-methyl-pentyl)-piperidin-4-yloxy]-pyrimidine;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-isopropoxy-propan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-isopropoxy-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-hydroxy-propan-1-one;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(5-pyridin-2-yl-thiophen-2-yl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(5-methyl-hexyl)-piperidin-4-yloxy]-pyrimidine;3-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-oxo-propane-1-sulfonicacid;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-(1-pentyl-piperidin-4-yloxy)-pyrimidine;4-(1-Butyl-piperidin-4-yloxy)-6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidine;4-{-4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-cyclohexanecarboxylicacid;1-(4-Diethylamino-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(2-methyl-4-phenyl-furan-3-yl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-(1-hexyl-piperidin-4-yloxy)-5-methyl-pyrimidine;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butyricacid;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-hexan-2-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-6-methyl-heptan-2-one;5-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-pentanoicacid;5-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-pentanenitrile;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-2-pyridin-2-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-4-yl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-ylmethyl}-acrylicacid;1-[1,4]Dioxan-2-yl-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxyl]-piperidin-1-yl}-ethanone;1-(2,3-Dihydro-[1,4]dioxin-2-yl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-p-tolyl-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-methoxy-phenyl)-ethanone;1-(2-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;3-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetyl)-benzonitrile;1-(2,4-Dimethyl-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Chloro-3-methyl-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Difluoromethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(5-phenyl-thiophen-2-yl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-aceticacid ethyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-2-ol;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(4-methoxy-cyclohexyl)-piperidin-4-yloxy]-5-methyl-pyrimidin;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-hexan-1-one;4-{6-[2-Fluoro-4-(2-isobutoxy-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Cyclopropoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Ethoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(3-methoxy-propoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-pyridin-2-yl-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(tetrahydro-pyran-4-yloxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-tert-Butoxy-ethoxy)-2-fluoro-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-sulfo-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-trifluoromethoxy-phenoxy)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-trifluoromethoxy-phenoxy)-5-prop-1-ynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-methoxy-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(6-methoxy-4-methyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[6-(2-isopropoxy-ethyl)-2-methyl-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenoxy)-5-ethynyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-4-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[5-Ethynyl-6-(2-fluoro-4-[1,2,4]triazol-1-yl-phenoxy)-pyrimidin-4-yloxy]-piperidin-1-yl}-3-pyridin-2-yl-propan-1-one;4-{5-Ethynyl-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yloxy}-3-fluoro-benzonitrile;5-Ethynyl-4-(2-fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidine;4-[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-ethynyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidine;4-[1-(3-Ethyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidine;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(3-methyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidine;4-[6-(2-Fluoro-4-methanesulfonylamino-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;cis-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid isopropyl ester;trans-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid isopropyl ester;N-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-3-methyl-butyramide;N-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-cyclohexyl}-isobutyramide;4-{6-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-Fluoro-6-(2-methanesulfonyl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Cyclopropyl-6-[2,5-difluoro-4-(2-hydroxy-ethyl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(5-Cyclopropyl-6-{2,5-difluoro-4-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(4-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Fluoro-ethyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; 4-{6-[2-Fluoro-4-(1-hydroxy-cyclopropylmethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2,5-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(R)-4-(6-{2-Fluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(S)-4-(6-{2-Fluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy)}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(R)-4-(5-Ethynyl-6-{2-fluoro-4-[2-(2-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;(S)-4-(2-{2-Fluoro-4-[2-(2-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-Fluoro-6-(2-morpholin-4-yl-ethyl)-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[4-fluoro-6-(2-methanesulfonyl-ethyl)-pyridin-3-yloxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2,5-Difluoro-4-(2-isopropoxy-ethyl)-phenoxy]-3-methyl-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-propionylsulfamoyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-sulfamoyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-sulfamoyl-ethyl)-phenoxy]-5-ethynyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,3-Difluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-{2-Fluoro-4-[2-(6-methoxy-pyridin-2-yl)-ethyl]-phenoxy}-3-methyl-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(3-methoxy-pyridin-2-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Fluoro-1-oxy-pyridin-4-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5′-Methoxy-6-methyl-[2,2′]bipyridinyl-5-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Ethynyl-6-[2-fluoro-4-(4-methoxy-pyridin-2-yl)-phenoxy]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(3-methoxy-pyridin-2-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2,5-Difluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester; and4-(6-({2,5-Difluoro-4-[2-(3-methoxy-piperidin-1-yl)-ethyl]-phenoxy}-5-ethynyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C8):4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-[6-(2-pyrrolidin-1-yl-ethyl)-pyridin-3-yl]-methanone;(6-Amino-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[5-Ethyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Isopropoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methyl-6-(2-methyl-6-pentyl-pyridin-3-yloxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-6-[1-(2-pyridin-3-yl-ethyl)-piperidin-4-yloxy]-pyrimidine;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;4-{6-[6-(2-Methoxy-ethanesulfonyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-Fluoro-4-methanesulfonyl-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine;4-(6-{2-Fluoro-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Iodo-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[N-(2-isopropoxy-ethyl)-carbamimidoyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carboxy-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(4-Bromo-2-fluoro-phenoxy)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methyl-pyrimidine;4-[6-(5-Methanesulfonyl-pyridin-2-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Cyclopropyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-oxo-butyricacid;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone;4-{6-[6-(2-Methoxy-ethylsulfanyl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-(2,5-Dimethoxy-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;4-[6-(6-Chloro-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-fluoro-phenyl)-ethanone;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethyl-phenyl)-ethanone;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-3-yl-ethanone;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-2-one;4-(6-{2-Fluoro-4-[(2-isopropoxy-ethylcarbamoyl)-methyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy)-piperidin-1]-yl}-1-(4-methanesulfonyl-phenyl)-ethanone;1-(4-Chloro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-acetyl)-benzonitrile;1-(3,4-Difluoro-phenyl)-2-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-pentan-1-one;4-[6-(2,4-Difluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-hexan-1-one;4-{6-[2-Fluoro-4-(2-methoxy-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(methoxy-methyl-carbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methoxy-propan-1-one;4-[6-(4-Cyano-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-(5-Aminomethyl-4,5-dihydro-oxazol-2-yl)-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methoxy-ethylamino)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(3-Methanesulfonyl-pyrrolidin-1-yl)-2-methyl-pyridin-3-yloxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Benzylamino-2-methyl-pyridin-3-yloxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-isopropoxy-ethylamino)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(6-{6-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-pyridin-3-yloxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-hydroxycarbamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-pyrrolidin-1-yl-ethylcarbamoyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(4-isopropyl-piperazine-1-carbonyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-morpholin-4-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carboxymethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Dimethylcarbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-sulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propionylsulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethynyl-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-phosphonooxy-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Bromo-6-(2-fluoro-4-methanesulfonyl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[2-(2-methanesulfonyl-pyrrolidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Carbamoylmethyl-2-fluoro-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-{[(tetrahydro-furan-2-ylmethyl)-carbamoyl]-methyl}-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-3-sulfamoyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;C-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-C-(4-fluoro-phenyl)-methyleneamine;3-tert-Butoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-propan-1-one;2-Ethoxy-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-(tetrahydro-furan-2-yl)-methanone;(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one;4-(6-{2-Fluoro-4-[2-(3-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-phenoxy}-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-morpholin-4-yl-2-oxo-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-imidazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(R)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-2-methylamino-butan-1-one;(S)-1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-hydroxy-butan-1-one;(R)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide;(S)—N-(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-acetamide;(R)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide;(S)—N-(2-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-1-methyl-2-oxo-ethyl)-acetamide;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (S)-tetrahydro-furan-3-yl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid (R)-tetrahydro-furan-3-yl ester;4-[6-(2-Amino-4-ethanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(1-{4-[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carbonyl}-2-methyl-propyl)-carbamicacid tert-butyl ester;4-{6-[2-Fluoro-4-(6-methoxy-pyridin-3-yl)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;3-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-4-methyl-pentan-1-one;2-Amino-1-{4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;4-{6-[2-Fluoro-4-(2-isopropoxy-ethoxy)-phenoxy]-5-methyl-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-[5-Methyl-6-(4-sulfo-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundsaccording to Formula (III) (referred to herein as Group C9):4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Cyclopropyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester; and4-({Cyclopropylmethyl-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022327 include the following compoundaccording to Formula (III) (referred to herein as Group C10):4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methyl-pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid isopropyl ester.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2004/022417 (published as WO 05/007658), the disclosure ofeach of which is herein incorporated by reference in its entirety.Disclosed in International Application No. PCT/US2004/022417 as a GPR119agonist is a compound of Formula (IV):

-   -   wherein:    -   A and B are each independently C₁₋₃ alkylene optionally        substituted with 1 to 4 substituents selected from the group        consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃        haloalkyl and halogen;    -   D is O, S, S(O), S(O)₂, CR₁R₂ or N—R₂, wherein R₁ is selected        from the group consisting of H, C₁₋₈ alkyl, C₁₋₄ alkoxy, halogen        and hydroxyl;    -   E is N, C or CR₃, wherein R₃ is H or C₁₋₈ alkyl;    -   is a single bond when E is N or CR₃, or a double bond when E is        C;    -   K is a C₃₋₆ cycloalkylene or C₁₋₃ alkylene wherein each are        optionally substituted with 1 to 4 substituents selected from        the group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano,        C₁₋₃ haloalkyl and halogen; or K is a bond;    -   Q is NR₄, O, S, S(O) or S(O)₂, wherein R₄ is H or C₁₋₈ alkyl and        the C₁₋₈ alkyl is optionally substituted with C₂₋₈ dialkylamine;    -   T is N or CR₅;    -   M is N or CR₆;    -   J is N or CR₇;    -   U is C or N;    -   V is N, CR₈ or V is a bond;    -   W is N or C;    -   X is O, S, N, CR₉ or NR₁₁;    -   Y is O, S, N, CR₁₀ or NR₁₂;    -   Z is C or N;    -   R₅, R₆, R₇, R₈, R₉ and R₁₀ are each independently selected from        the group consisting of H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄        alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈        dialkylamino, carboxamide, cyano, C₃₋₆ cycloalkyl, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen, C₁₋₄        haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄        haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, hydroxylamino        and nitro; wherein said C₂₋₆ alkenyl, C₁₋₈ alkyl, C₂₋₆ alkynyl        and C₃₋₆ cycloalkyl are optionally substituted with 1, 2, 3 or 4        substituents selected from the group consisting of C₁₋₅ acyl,        C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄ alkylamino, C₁₋₄        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈        dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro;    -   R₁₁ and R₁₂ are each independently selected from C₂₋₆ alkenyl,        C₁₋₈ alkyl, C₂₋₆ alkynyl or C₃₋₆ cycloalkyl each optionally        substituted with 1, 2, 3 or 4 substituents selected from the        group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₄        alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄ alkylthiocarboxamide,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl;        C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₂₋₈        dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄        dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄        alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄        haloalkylthio, halogen, hydroxyl, hydroxylamino and nitro;    -   Ar₁ is aryl or heteroaryl each optionally substituted with R₁₃,        R₁₄, R₁₅, R₁₆, and R₁₇; wherein R₁₃ is selected from the group        consisting of C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy,        C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        arylsulfonyl, carbamimidoyl, carbo-C₁₋₆ alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆        dialkylthiocarboxamide, guanidinyl, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heterocyclic, heterocyclic-oxy,        heterocyclicsulfonyl, heterocyclic-carbonyl, heteroaryl,        heteroarylcarbonyl, hydroxyl, nitro, C₄₋₇ oxo-cycloalkyl,        phenoxy, phenyl, sulfonamide, sulfonic acid, and thiol, and        wherein said C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy, C₁₋₈        alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylsulfonamide, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆        dialkylamino, heterocyclic, heterocyclic-carbonyl, heteroaryl,        phenoxy and phenyl are optionally substituted with 1 to 5        substituents selected independently from the group consisting of        C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl,        C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆        dialkylamino, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,        C₁₋₄ haloalkylthio, heteroaryl, heterocyclic, hydroxyl, nitro,        phenyl, and phosphonooxy, and wherein said C₁₋₇ alkyl and C₁₋₄        alkylcarboxamide are each optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₄ alkoxy        and hydroxy; or    -   R₁₃ is a group of Formula (IVA):

-   -   -   wherein:            -   “p” and “r” are independently 0, 1, 2 or 3; and            -   R₁₈ is H, C₁₋₅ acyl, C₂₋₆ alkenyl, C₁₋₈ alkyl, C₁₋₄                alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide,                carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇                cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, heteroaryl                or phenyl, and wherein said heteroaryl or phenyl                optionally substituted with 1 to 5 substituents selected                independently from the group consisting of C₁₋₄ alkoxy,                amino, C₁₋₄ alkylamino, C₂₋₆ alkynyl, C₂₋₈ dialkylamino,                halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl and hydroxyl;

    -   R₁₄, R₁₅, R₁₆, and R₁₇ are each independently selected form the        group consisting of H, C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl,        C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,        C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,        C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide,        carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,        halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄        haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,        hydroxyl and nitro; or

    -   two adjacent R₁₄, R₁₅, R₁₆ and R₁₇ together with the atoms to        which they are attached form a 5, 6 or 7 member cycloalkyl,        cycloalkenyl or heterocyclic group fused with Ar₁ wherein the 5,        6 or 7 member group is optionally substituted with halogen; and

    -   R₂ is selected from the group consisting of C₁₋₈ alkyl, C₂₋₆        alkynyl, amino, aryl, carboxamide, carboxy, cyano,        C₃₋₆-cycloalkyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,        heteroaryl and hydroxyl; and wherein said C₁₋₈ alkyl, aryl and        heteroaryl are each optionally substituted with 1 to 5        substituents selected from the group consisting of C₁₋₅ acyl,        C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄        alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄        alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄        alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,        C₃₋₆-cycloalkyl-C₁₋₃-heteroalkylene, C₂₋₈ dialkylamino, C₂₋₆        dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆        dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄        haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄        haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,        hydroxylamino and nitro; or

    -   R₂ is —Ar₂—Ar₃ wherein Ar₂ and Ar₃ are each independently aryl        or heteroaryl each optionally substituted with 1 to 5        substituents selected from the group consisting of H, C₁₋₅ acyl,        C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,        C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfinyl, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, amino, C₁₋₄ alkylamino,        carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆-cycloalkyl,        C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₁₋₄ haloalkoxy,        C₁₋₄ haloalkyl, halogen, hydroxyl and nitro; or

    -   R₂ is a group of Formula (IVB):

-   -   -   wherein:            -   R₁₉ is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl, heteroaryl                or OR₂₁; and R₂₀ is F, Cl, Br, CN or NR₂₂R₂₃; where R₂₁                is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, and R₂₂ and R₂₃ are                independently H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, aryl or                heteroaryl;

or

-   -   R₂ is a group of Formula (IVC):

-   -   wherein:    -   G is:    -   i) —C(O)—, —C(O)NR₂₅—, —NR₂₅C(O)—, —NR₂₅—, —NR₂₅C(O)O—,        —OC(O)NR₂₅—, —CR₂₅R₂₆NR₂₇C(O)—, —CR₂₅R₂₆C(O)NR₂₇—, —C(O)O—,        —OC(O)—, —C(S)—, —C(S)NR₂₅—, —C(S)O—, —OC(S)—, —CR₂₅R₂₆—, —O—,        —S—, —S(O)—, —S(O)₂— or a bond when D is CR₂R₃; or    -   ii) —CR₂₅R₂₆C(O)—, —C(O)—, —CR₂₅R₂₆C(O)NR₂₇—, —C(O)NR₂₅—,        —C(O)O—, —C(S)—, —C(S)NR₂₅—, —C(S)O—, —CR₂₅R₂₆—, —S(O)₂—, or a        bond when D is NR₂;

wherein R₂₅, R₂₆ and R₂₇ are each independently H or C₁₋₈ alkyl; and R₂₄is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, or heterocycliceach optionally substituted with 1 to 5 substituents selected from thegroup consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy,C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heteroaryl, heterocyclic,hydroxyl, hydroxylamino, nitro, phenyl, phenoxy, and sulfonic acid,wherein said C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, heteroaryl,phenyl and phenoxy are each optionally substituted with 1 to 5substituents selected from the group consisting of C₁₋₅ acyl, C₁₋₅acyloxy, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heterocyclic, hydroxyl, hydroxylamino, nitro, and phenyl;

-   -   provided that Z and U are not both N.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D1):4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-3,6-dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isobutyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-(4-Methanesulfonyl-phenyl)-4-(piperidin-4-yloxy)-1H-pyrazolo[3,4-d]pyrimidine;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone;(3-Fluoro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(1-tert-Butyl-5-methyl-1H-pyrazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-tert-Butyl-2-methyl-2H-pyrazol-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid isobutyl ester;Furan-2-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(1-methyl-1H-pyrrol-2-yl)-methanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-3-yl-ethanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(2-methyl-pyridin-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-methyl-pyridin-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-isoxazol-3-yl)-methanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-thiophen-2-yl-ethanone;4-(1-Benzyl-azetidin-3-yloxy)-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethyl-butan-2-one;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyrazin-2-yl-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-pyrazin-2-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyrimidin-5-yl-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-pyridazin-4-yl-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-thiophen-2-yl-methanone;(3,4-Dimethyl-isoxazol-5-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;3-tert-Butoxy-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-propan-1-one;(3-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-3-oxo-propyl)-methyl-carbamicacid tert-butyl ester;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-trifluoromethyl-pyridin-3-yl)-methanone;{(4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane-1,4-diamine;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-methyl-[1,2,3]thiadiazol-5-yl)-methanone;(3,5-Dimethyl-isoxazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(2,5-Dimethyl-2H-pyrazol-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(3-methyl-isoxazol-5-yl)-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid pyridin-4-ylamide;N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-nicotinamide;3-tert-Butoxy-N-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-propionamide;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;(3,5-Dimethyl-isoxazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,5-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[1-(3,5-Bis-trifluoromethyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-azetidine-1-carboxylicacid isopropyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid propyl ester;4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;{4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;{4-[1-(3-Fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexyl}-carbamicacid tert-butyl ester;N-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane-1,4-diamine;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(6-methyl-pyridin-3-yl)-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(2-methyl-pyridin-3-yl)-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-pyridin-3-yl-methanone;{3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidin-1-yl}-(1-methyl-1H-pyrrol-3-yl)-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-cyclohexyl}-carbamicacid tert-butyl ester;N-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-cyclohexane-1,4-diamine;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-trifluoromethyl-pyridin-3-yl)-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclohexyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-pyran-4-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclopentyl, ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-furan-3-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-furan-3-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tetrahydro-thiopyran-4-yl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclobutyl ester;(6-tert-Butyl-pyridin-3-yl)-{(4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-methyl}-cyclohexyl)-carbamicacid tert-butyl ester;N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexylmethyl}-nicotinamide;N-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-cyclohexylmethyl}-6-methyl-nicotinamide;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-({[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester;3-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-{1-[2-(2-Dimethylamino-ethoxy)-4-methanesulfonyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid tert-butyl ester;3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid pyridin-3-ylmethyl esteracid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-pyridin-3-yl-ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 3-pyridin-3-yl-propyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-dimethylamino-ethyl ester;4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2,4-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[6-Dimethylamino-1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;1-(4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-piperidin-1-yl)-3,3-dimethyl-butan-2-one;4-{[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-piperidine-1-carboxylicacid cyclobutyl ester; and4-[({1-[4-(2-Methanesulfonyl-ethyl)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D2):4-({[1-(2,5-Difluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone;2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-fluoro-phenyl)-ethanone;2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-pyridin-2-yl-ethanone;(2,5-Dimethyl-furan-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-({(2-Dimethylamino-ethyl)-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({(2-Dimethylamino-ethyl)-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Dimethylamino-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-{2-Ethyl-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amino}-ethyl)-piperazine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester;4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-ethyl}-piperazine-1-carboxylicacid ethyl ester;4-{2-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-propyl}-piperazine-1-carboxylicacid ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfanyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine-4-sulfonyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 2-methoxy-ethyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 3,3-dimethyl-butyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 4-methyl-pentyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid cyclopropylmethyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid cyclobutylmethyl ester;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid 2-cyclopropyl-ethyl ester;(5-Bromo-furan-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-morpholin-4-ylmethyl-furan-2-yl)-methanone;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid pentyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 1-ethyl-propyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-ethyl-butyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid cyclopentylmethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-pyrrolidin-1-yl-ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2-morpholin-4-ylethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid ethyl ester;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 2,2-dimethyl-propyl ester;(5-Butyl-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-4-ylmethyl)-amine;Ethyl-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-amine;[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-(5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-amine;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;5′-Fluoro-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-6′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine;[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yl]-amine;(4-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-pyrrolidin-3-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;(5′-Fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-amine;(5-Bromo-pyridin-3-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid tert-butyl ester;3-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-pyrrolidine-1-carboxylicacid isopropyl ester;(6-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Chloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanone;(2-Chloro-pyridin-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Hydroxy-3-methoxy-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Chloro-3-nitro-phenyl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-3-methyl-butan-1-one;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-pyrazol-1-yl-pyridin-3-yl)-methanone;(2-Hydroxy-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5,6-Dichloro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Bromo-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-nicotinicacid;(1H-Imidazol-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;3-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-pyrrolidine-1-carboxylicacid tert-butyl ester;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-pyrrolidin-1-yl-pyridin-3-yl)-methanone;(6-Isobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Ethylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Cyclobutylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Isopropylamino-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;[6-(1-Ethyl-propylamino)-pyridin-3-yl]-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-[6-(1-propyl-butylamino)-pyridin-3-yl]-methanone;5-Benzyloxy-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-pyran-4-one;Benzo[c]isoxazol-3-yl-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Chloro-pyridin-2-yl)-{4-[1-(1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Iodo-pyridimin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;1-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-butan-2-one;2-(5-Bromo-pyridin-3-yl)-1-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;(6-Fluoro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Fluoro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Chloro-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(2-Chloro-5-fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-[5-(2-methyl-pyrrolidin-1-ylmethyl)-pyridin-3-yl]-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(6-methyl-pyridin-2-yl)-methanone;5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-nicotinonitrile;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-methoxy-pyridin-2-yl)-methanone;(2-Fluoro-pyridin-4-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(2-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Fluoro-pyridin-3-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-methoxy-thiophen-3-yl)-methanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-pyran-4-one;(5-Ethyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(4-Ethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-pyridin-2-yl-thiophen-2-yl)-methanone;(5-Amino-pyridin-2-yl)-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Amino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl})-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-[5-(3-methyl-butylamino)-pyridin-2-yl]-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(4-trifluoromethoxy-phenyl)-methanone;(5-Butyl-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(5-Ethylamino-pyridin-2-yl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-isopropoxymethyl-pyridin-2-yl)-methanone;(4-Difluoromethoxy-phenyl)-{4-[1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(5-isopropoxy-pyridin-2-yl)-methanone;5-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carbonyl}-pyridine-2-carboxylicacid methyl ester;{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-aceticacid ethyl ester;{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-(3-trifluoromethoxy-phenyl)-methanone;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Chloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;2-{4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-1-(3-trifluoromethyl-phenyl)-ethanone;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5′-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;1-(4-Methanesulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(4-trifluoromethoxy-phenyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Chloro-3-methyl-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(3,4-Dichloro-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;5′-Bromo-4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-trifluoromethoxy-phenyl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(4-Methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-5′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;1-(2,4-Dimethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Difluoromethoxy-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;1-(4-Diethylamino-phenyl)-2-{4-[1-(4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-ethanone;(2-{4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidin-1-yl}-5-methyl-pyrimidin-4-yl)-dimethyl-amine;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(5-methyl-4-pyrrolidin-1-yl-pyrimidin-2-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Methyl-4-propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Isopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Methyl-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{1-[4-(2-Methoxy-ethylamino)-2-methyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Bromo-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Propylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(1-{2-Methyl-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Cyclopropylamino-2-methyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{-[4-(2-Dimethylamino-ethylamino)-2-methyl-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[1-(2-Fluoro-4-morpholin-4-yl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-isopropylamino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[(2-Methanesulfonyl-ethyl)-methyl-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{1-[4-(2-Methoxy-ethylamino)-phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[(Tetrahydro-furan-2-ylmethyl)-amino]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-(1-{4-[4-(2-Methanesulfonyl-ethyl)-piperazin-1-yl]-phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Amino-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-({[1-(2-Fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-ylsulfanyl]-1-(2-fluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(2-Fluoro-4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-propionylsulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Cyano-2-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;1-(2,5-Difluoro-4-methoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Fluoro-6-methoxy-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(6-Methoxy-2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2,5-Difluoro-4-sulfamoyl-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-hydroxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-(6-methoxy-2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;1-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzonitrile;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;1-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-(6-methoxy-2-methyl-pyridin-3-yl)-1H-pyrazolo[3,4-d]pyrimidine;2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-benzenesulfonamide;4-[1-(2-Fluoro-4-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(4-Difluoromethoxy-2-fluoro-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2-Fluoro-4-trifluoromethoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[1-(2,5-Difluoro-4-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[3,4-d]pyrimidin-1-yl}-phenol;1-(2-Fluoro-4-methoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Difluoromethoxy-2-fluoro-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2-Fluoro-4-trifluoromethoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(2,5-Difluoro-4-methoxy-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1H-pyrazolo[3,4-d]pyrimidine;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl}-cyclohexyloxy]-pyrazolo[3,4-d]pyrimidin-1-yl)-phenol;1-(2-Fluoro-4-methoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;1-(4-Difluoromethoxy-2-fluoro-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine;and1-(2-Fluoro-4-trifluoromethoxy-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1H-pyrazolo[3,4-d]pyrimidine.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D3):4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isobutyl ester;{4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidin-1-yl}-pyridin-3-yl-methanone;4-[9-(4-Methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[9-(6-Methanesulfonyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid tert-butyl ester and4-[9-(2-Fluoro-4-methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D4):4-[9-(2-Fluoro-4-propionylsulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(4-Cyano-2-fluoro-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(2-Fluoro-4-sulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;9-(2-Fluoro-4-methanesulfonyl-phenyl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9H-purine;3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-(6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl)-benzonitrile;3-Fluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl}-benzenesulfonamide;4-[9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(4-Fluoro-6-methoxy-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(6-Methoxy-2-methyl-pyridin-3-yl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[9-(2,5-Difluoro-4-sulfamoyl-phenyl)-9H-purin-6-yloxy]-piperidine-1-carboxylicacid isopropyl ester;9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9H-purine;9-(4-Fluoro-6-methoxy-pyridin-3-yl)-6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9H-purine;6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-9-(6-methoxy-2-methyl-pyridin-3-yl)-9H-purine;2,5-Difluoro-4-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-purin-9-yl}-benzenesulfonamide;9-(2-Fluoro-4-methanesulfonyl-phenyl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9H-purine;3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-benzonitrile;3-Fluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-benzenesulfonamide;9-(2,5-Difluoro-4-methanesulfonyl-phenyl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9H-purine;9-(4-Fluoro-6-methoxy-pyridin-3-yl)-6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9H-purine;6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-9-(6-methoxy-2-methyl-pyridin-3-yl)-9H-purine;and2,5-Difluoro-4-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-purin-9-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundaccording to Formula (IV) (referred to herein as Group D5):4-[3-(4-Methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D6):3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-Fluoro-4-({7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide;4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine;and2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundaccording to Formula (IV) (referred to herein as Group D7):4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid tert-butyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D8):4-({Ethyl-[3-(4-methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-ylsulfanyl]-piperidine-1-carboxylicacid tert-butyl ester; and4-[3-(4-Methanesulfonyl-phenyl)-isoxazolo[4,5-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundaccording to Formula (IV) (referred to herein as Group D9):4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-[1,7]naphthyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D10):4-[8-(2-Fluoro-4-methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Methylsulfanyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Isopropoxy-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Bromo-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-propionylsulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Cyano-2-fluoro-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-sulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Fluoro-6-methoxy-pyridin-3-yl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(6-Methoxy-2-methyl-pyridin-3-yl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-sulfamoyl-phenyl)-quinolin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-benzenesulfonamide;4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-quinoline;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinoline;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinoline;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-benzenesulfonamide;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-benzonitrile;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin-8-yl}-N-propionyl-benzenesulfonamide;8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-quinolin;2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-benzenesulfonamide;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-quinoline;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-1-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinoline;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinoline;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-benzenesulfonamide;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-benzonitrile;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinolin-8-yl}-N-propionyl-benzenesulfonamide;and8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-quinoline.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D11):4-[8-(2-Fluoro-4-methanesulfonyl)-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-propionylsulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Cyano-2-fluoro-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2-Fluoro-4-sulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(4-Fluoro-6-methoxy-pyridin-3-yl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[8-(2,5-Difluoro-4-sulfamoyl-phenyl)-pyrido[3,4-d]pyrimidin-4-yloxy]1-piperidine-1-carboxylicacid isopropyl ester;8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzonitrile;3-Fluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidine;4-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidine;2,5-Difluoro-4-{4-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;8-(2-Fluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzonitrile;3-Fluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide;8-(2,5-Difluoro-4-methanesulfonyl-phenyl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;8-(4-Fluoro-6-methoxy-pyridin-3-yl)-4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidine;4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-8-(6-methoxy-2-methyl-pyridin-3-yl)-pyrido[3,4-d]pyrimidine;and2,5-Difluoro-4-{4-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrido[3,4-d]pyrimidin-8-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D12):3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl}-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl)-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidine;2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidine;7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-pyrazolo[1,5-a]pyrimidin;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl]-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy-2-methyl-pyrazolo1,5-a]pyrimidin-3-yl}-benzenesulfonamide;7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-pyrazolo-[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl}-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl)-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-pyrazolo[1,5-a]pyrimidine;and2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-pyrazolo[1,5-a]pyrimidin-3-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D13):4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-(7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine;and2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2004/022417 include the following compoundsaccording to Formula (IV) (referred to herein as Group D14):4-[3-(2-Fluoro-4-methanesulfonyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-propionylsulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Cyano-2-fluoro-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2-Fluoro-4-sulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(4-Fluoro-6-methoxy-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(6-Methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-(2,5-Difluoro-4-sulfamoyl-phenyl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-yloxy]-piperidine-1-carboxylicacid isopropyl ester;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;7-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;2,5-Difluoro-4-{7-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2-Fluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-N-propionyl-benzenesulfonamide;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzonitrile;3-Fluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide;3-(2,5-Difluoro-4-methanesulfonyl-phenyl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;3-(4-Fluoro-6-methoxy-pyridin-3-yl)-7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;7-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-3-(6-methoxy-2-methyl-pyridin-3-yl)-2-methyl-2H-pyrazolo[4,3-d]pyrimidine;and2,5-Difluoro-4-{7-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-2-methyl-2H-pyrazolo[4,3-d]pyrimidin-3-yl}-benzenesulfonamide.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US2005/019318 (published as WO 2005/121121), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2005/019318 as a GPR119 agonist is acompound of Formula (V):

or N-oxide thereof;

wherein:

-   -   A₁ and A₂ are independently C₁₋₃ alkylene optionally substituted        with one or more substituents selected independently from the        group consisting of C₁₋₆ alkyl, C₁₋₆ alkoxy, and carboxy;    -   D is CR₁R₂ or NR₂, wherein R₁ is selected from the group        consisting of H, C₁₋₆ alkyl, C₁₋₆ alkoxy, halogen and hydroxyl;    -   E is N, C or CR₃, wherein R₃ is H or C₁₋₆ alkyl;    -   is a single bond when E is N or CR₃, or a double bond when E is        C;    -   K is absent, C₃₋₆ cycloalkylene, or C₁₋₃ alkylene group        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ alkyl, C₁₋₆        alkoxy, carboxy, cyano, and halogen;    -   Q₁ is NR₄, O, S, S(O) or S(O)₂, wherein R₄ is H, C₁₋₆ acyl, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, or        C₃₋₇-cycloalkyl-C₁₋₃-alkylene, wherein said C₁₋₆ alkyl is        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₄-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido, C₁₋₆        haloalkoxy, C₁₋₄ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,        hydroxylamino and nitro;    -   Q₂ is absent, NR₅, or O, wherein R₅ is H, C₁₋₆ acyl, C₁₋₆ alkyl,        C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₇ cycloalkyl, or        C₃₋₇-cycloalkyl-C₁₋₃-alkylene, wherein said C₁₋₆ alkyl is        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide,        carboxy, cyano, C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,        hydroxylamino and nitro;    -   W is N or CH;    -   X is N or CR₆;    -   Y is N or CR₇;    -   Z is N or CR₈;    -   V is absent, C₁₋₃ heteroalkylene, or C₁₋₃ alkylene wherein each        are optionally substituted with one or more substituents        selected independently from the group consisting of C₁₋₃ alkyl,        C₁₋₆ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, and halogen;    -   R₆, R₇, and R₈ are each independently selected from the group        consisting of H; C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆        alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆        alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆        alkylthioureyl, C₁₋₆ alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆        alkoxycarbonyl, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide,        di-C₁₋₆-alkylthiocarboxamido, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,        halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆        haloalkylthio, hydroxyl, hydroxylamino and nitro, wherein said        C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl and C₃₋₆ cycloalkyl are        each optionally substituted with one or more substituents        independently selected from the group consisting of C₁₋₆ acyl,        C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆        alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆        alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆        alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆        alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl,        carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide,        di-C₁₋₆-alkylthiocarboxamido, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,        halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆        haloalkylthio, hydroxyl, hydroxylamino and nitro;    -   Ar is aryl or heteroaryl optionally substituted with R₉-R₁₃;    -   R₉ is selected from the group consisting of C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, aryl, arylcarbonyl, arylsulfonyl, di-C₁₋₆-alkylamino,        carbamimidoyl, C₁₋₆ alkoxycarbonyl, carboxamide, carboxy, cyano,        C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido,        guanidine, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆        haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio,        heterocyclic, heterocyclicsulfonyl, heteroaryl, hydroxyl,        hydroxylamino, nitro, C₃₋₆ oxo-cycloalkyl, phenoxy, sulfonamide,        sulfonic acid and thiol; and wherein each available R₉ is        optionally substituted with one or more substituents selected        independently from the group consisting of C₁₋₆ acyl, C₁₋₆        acylsulfonamide, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆        alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl,        C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,        C₁₋₆ alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆ alkylthioureyl,        C₁₋₆ alkylureyl, amino; aryl, arylcarbonyl, arylsulfonyl,        di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide, carboxy,        cyano, C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl,        heteroarylcarbonyl, heteroarylsulfonyl, heterocyclic, hydroxyl,        hydroxylamino, and nitro;    -   R₁₀-R₁₃ are independently selected from the group consisting of        C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,        C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆        alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆        alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆        alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl,        carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide,        di-C₁₋₆-alkylthiocarboxamido, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl,        halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl. C₁₋₆        haloalkylthio, hydroxyl, hydroxylamino, nitro, and thiol; or two        adjacent groups together with the atoms to which they are bonded        form a 5, 6 or 7 member cycloalkyl, cycloalkenyl or heterocyclic        group wherein the 5, 6 or 7 member group is optionally        substituted with halogen or oxo; and    -   R₂ is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆        acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino,        C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆        alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆        alkylthiocarboxamide, C₁₋₆ alkylthioureyl, C₁₋₆ alkylureyl,        amino, aryl, arylcarbonyl, aryloxy, di-C₁₋₆-alkylamino,        carbamimidoyl, C₁₋₆ alkoxycarbonyl, C₃₋₇-cycloalkoxycarbonyl,        carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide,        di-C₁₋₆-alkylthiocarboxamido, guanidine, C₁₋₆ haloalkoxy, C₁₋₆        haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl, C₁₋₆        haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl,        heteroaryl-C₁₋₃-alkylene, heteroarylcarbonyl, heteroaryloxy,        heterocycliccarboxamide, hydroxyl, hydroxylamino and nitro;        wherein each available R₂ is optionally substituted with one or        more substituents selected independently from the group        consisting of C₁₋₆ acyl, C₁₋₄ acyloxy, C₂₋₆ alkenyl, C₁₋₆        alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide, C₂₋₆        alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆        alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylthiocarboxamide, C₁₋₆        alkylthioureyl, C₁₋₆ alkylureyl, amino, aryl,        di-C₁₋₆-alkylamino, C₁₋₆ alkoxycarbonyl, carboxamide, carboxy,        cyano, C₃₋₆ cycloalkyl, di-C₁₋₆-alkylcarboxamide,        di-C₁₋₆-alkylsulfonamide, di-C₁₋₆-alkylthiocarboxamido, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclic,        heteroaryl, hydroxyl, hydroxylamino and nitro, and wherein C₁₋₆        alkyl is further optionally substituted with one or more        substituents selected independently from the group consisting of        C₁₋₆ acyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ alkylcarboxamide,        C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl; C₁₋₆ alkylsulfonyl,        C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, di-C₁₋₆-alkylamino, C₁₋₆        alkoxycarbonyl, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,        di-C₁₋₆-alkylcarboxamide, di-C₁₋₆-alkylsulfonamide, C₁₋₆        haloalkoxy, C₁₋₆ haloalkyl, halogen, C₁₋₆ haloalkylsulfinyl,        C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclic,        hydroxyl, hydroxylamino and nitro.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2005/019318 include the following compoundsaccording to Formula (V) (referred to herein as Group E1):4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-6-(4-methanesulfonyl-phenoxy)-pyrimidine;{6-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-(4-methanesulfonyl-phenyl)-amine;4-{[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-benzylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[(Benzo[1,3]dioxol-5-ylmethyl)-amino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-fluoro-phenoxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;4-({Methyl-[6-(2-pyridin-4-yl-ethylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(2-pyridin-3-yl-ethylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[(2-Fluoro-4-methanesulfonyl-phenyl)-methyl-amino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[4-(2-Methanesulfonyl-ethyl)-phenylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethylsulfanyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Isopropylsulfanyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-methylsulfamoyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Dimethylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-methylsulfamoylmethyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-sulfamoyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-[1,2,4]triazol-1-yl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-[1,2,4]triazol-1-ylmethyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-(6-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenylamino]-pyrimidin-4-yl)-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(Benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(6-Methanesulfonyl-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[4-(2-oxo-oxazolidin-4-ylmethyl)-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[4-(1,1-Dioxo-1λ6-thiomorpholin-4-ylmethyl)-phenylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-pyrazol-1-yl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,2-Difluoro-benzo[1,3]dioxol-5-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(4-trifluoromethanesulfonyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[4-(morpholine-4-sulfonyl)-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-{6-[2-(pyridine-2-carbonyl)-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-5-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;N-Ethyl-3-fluoro-4-[6-(methyl-piperidin-4-ylmethyl-amino)-pyrimidin-4-ylamino]-benzenesulfonamide;3-Fluoro-N-isopropyl-4-[6-(methyl-piperidin-4-ylmethyl-amino)-pyrimidin-4-ylamino]-benzenesulfonamide;4-({[6-(3,4-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,6-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,3-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(2,3,5-trifluoro-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,4-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-(6-[2-(1-oxy-pyridin-3-yl)-ethylamino]-pyrimidin-4-yl)-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[(Methyl-(6-[2-(1-oxy-pyridin-3-yl)-ethylamino]-pyrimidin-4-yl)-amino)-methyl]-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-[({6-[2-(2-Fluoro-phenoxy)-ethylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[2-(2-Chloro-phenoxy)-ethylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Chloro-phenoxy)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[2-(4-Fluoro-phenoxy)-propylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethylsulfamoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-isopropylsulfamoyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(5-Carboxy-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,6-Dimethoxy-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;6-{6-[(1-tert-Butoxycarbonyl-piperidin-4-ylmethyl)-methyl-amino]-pyrimidin-4-ylamino}-nicotinicacid;4-({[6-(6-Acetylamino-pyridin-3-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(5-Fluoro-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Cyano-2-ethyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Butyryl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(5-Bromo-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3-Bromo-5-methyl-pyridin-2-ylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Methyl-[6-(5-trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Bromo-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(3-Carboxy-4-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(4-Ethoxycarbonyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Carboxy-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid butyl ester;4-({[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid cyclopropylmethyl ester;(4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperazin-1-yl)-aceticacid ethyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-(6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperazin-1-yl]-pyrimidin-4-yl)-amine;4-({[6-(2,5-Difluoro-4-hydroxy-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(4-Ethylcarbamoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-[({6-[2-Fluoro-4-(N-hydroxycarbamimidoyl)-phenylamino]-pyrimidin-4-yl}-methyl-amino)-methyl]-piperidine-1-carboxylicacid isobutyl ester:4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid 3-methyl-butyl ester;4-({[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;(5-Butyl-pyridin-2-yl)-[4-({[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidin-1-yl]-methanone;N-(2-Fluoro-4-methanesulfonyl-phenyl)-N′-(5′-fluoro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl)-N′-methyl-pyrimidine;-4,6-diamine;4-({[6-(4-Carbamimidoyl-2-fluoro-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1carboxylic acid cyclobutyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-piperidine-1-carboxylicacid tert-butyl ester;N-(2-Fluoro-4-methanesulfonyl-phenyl)-N′-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperidin-4-ylmethyl]-N′-methyl-pyrimidine;-4,6-diamine;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid 1-ethyl-propyl ester;4-({Ethyl-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Amino-2,5-difluoro-phenoxy)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-4-methoxy-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({Ethyl-[6-(2,4,5-trifluoro-phenylamino)-pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;4-[(Ethyl-{6-[4-(N-ethylcarbamimidoyl)-2,5-difluoro-phenylamino]-pyrimidin-4-yl}-amino)-methyl]-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yl]-ethyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[({6-[5-(2-Amino-ethylamino)-4-cyano-2-fluoro-phenylamino]-pyrimidin-4-yl}-ethyl-amino)-methyl]-piperidine-1-carboxylicacid isopropyl ester;{1-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperidin-4-yl}-aceticacid methyl ester;3-{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-piperazin-1-yl}-propionicacid ethyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-(6-[4-(4-isobutyl-phenyl)-piperidin-1-yl]-pyrimidin-4-yl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropyl-phenyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;{6-[4-(3-Cyclopropylmethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isobutyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropoxy-phenyl)-piperazin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(4-isopropoxy-phenyl)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(5-isopropoxy-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-amine;{6-[4-(3-Dimethylaminomethyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl}-(2-fluoro-4-methanesulfonyl-phenyl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-(6-{4-[2-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-piperazin-1-yl}-pyrimidin-4-yl)-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(5-isopropoxy-pyridin-2-yloxy)-piperidin-1-yl]-pyrimidin-4-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-(6-[4-(3-pyridin-3-yl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-pyrimidin-4-yl)-amine;2,5-Difluoro-4-{6-[4-(4-isopropoxy-phenyl)-piperazin-1-yl]-pyrimidin-4-ylamino}-benzonitrile;4-{[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-{[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-ylamino]-methyl}-piperidine-1-carboxylicacid isopropyl ester;4-({[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-({[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester; and4-({[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-4-yl]-methyl-amino}-methyl)-piperidine-1-carboxylicacid isobutyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US2005/019318 include the following compoundsaccording to Formula (V) (referred to herein as Group E2):4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-ylmethyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(6-Chloro-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;(6-Bromo-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-(6-methyl-pyridin-2-yl)-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-(6-fluoro-pyridin-2-yl)-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-pyridin-2-yl-methanone;(5-Bromo-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;{4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-(5-methyl-pyridin-3-yl)-methanone;(5,6-Dichloro-pyridin-3-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,5-Difluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,4,5-Trifluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Fluoro-4-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Hydroxy-4-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Cyano-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Chloro-4-cyano-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Chloro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3-Fluoro-4-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(3,4-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Cyano-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-5-ethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Ethoxy-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Ethylsulfanyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Isopropylsulfanyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;(5-Butyl-pyridin-2-yl)-{4-[6-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone;4-[6-(5-Chloro-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Acetylamino-4-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(5-Fluoro-4-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methoxy-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methoxy-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Fluoro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Chloro-6-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Chloro-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Fluoro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Chloro-4-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(5-Fluoro-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Fluoro-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(6-Chloro-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Methyl-pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(4-Chloro-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2,5-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-3-methoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Fluoro-4-hydroxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-isopropoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-[6-(5′-isopropoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yloxy)-pyrimidin-4-yl]-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;4-[6-(4-Cyano-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(Pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acidisopropyl ester;4-[6-(Pyridin-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acidisopropyl ester;4-[6-(2,5-Difluoro-4-propoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Ethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Dimethylamino-2-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-isopropylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-6-propylamino-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Isopropylamino-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-6-propoxy-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Iodo-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-iodo-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[Methyl-(2-methyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-amino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Phenyl-2H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-tert-Butyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-p-Tolyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methoxy-5-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Acetylamino-3-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Chloro-4-fluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3,5-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-quinolin-6-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methylsulfanyl-benzothiazol-6-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Morpholin-4-yl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Benzenesulfonyl-thiophen-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Piperidin-1-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Oxo-5,6,7,8-tetrahydro-naphthalen-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methyl-1H-pyrazolo[3,4-b]pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Cyano-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Methyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Cyclopropyl-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methoxy-2-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,4-Dimethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[Acetyl-(2-fluoro-4-methanesulfonyl-phenyl)-amino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Carbamoyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(3,4-Difluoro-phenyl)-thiazol-2-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Oxo-1-phenyl-4,5-dihydro-1H-pyrazol-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Oxazol-5-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Trifluoromethyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Chloro-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[(5-Pyridin-2-yl-thiophen-2-ylmethyl)-amino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[5-(4-Chloro-phenyl)-2H-pyrazol-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(1-Oxo-indan-5-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[5-(1-Methyl-pyrrolidin-2-yl)-pyridin-2-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methoxy-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(5-Bromo-3-methyl-pyridin-2-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Chloro-6-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Ethynyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2-trifluoromethoxy-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3-Iodo-4-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-5-methyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[5-(4-Methoxy-phenyl)-[1,3,4]thiadiazol-2-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(3,5-Dimethyl-isoxazol-4-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-4-morpholin-4-yl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Methyl-4-propylamino-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[4-(2-Dimethylamino-ethoxy)-2,5-difluoro-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethoxy)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,4-Difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,4,5-Trifluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[Acetyl-(4-methanesulfonyl-phenyl)-amino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;(2,5-Difluoro-4-propoxy-phenyl)-{6-[1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine;4-{6-[2,5-Difluoro-4-(morpholin-4-ylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-methoxy-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2,5-Difluoro-4-[(tetrahydro-furan-2-ylmethyl)-amino]-phenylamino}-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Butylamino-2,5-difluoro-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-({6-[2,5-Difluoro-4-(3-methyl-butylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-2-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(2-morpholin-4-yl-ethylamino)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester:4-{6-[2-(2,5-Difluoro-phenoxy)-ethylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2,5-Difluoro-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Bromo-2-fluoro-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-morpholin-4-yl-phenoxy)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2,5-Difluoro-4-(tetrahydro-furan-2-ylmethoxy)-phenylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-3-yloxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[4-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-2-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester.

Examples of GPR119 agonists are described in International. ApplicationNo. PCT/GB2004/050046 (published as WO 2005/061489), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/GB2004/050046 as a GPR119 agonist is acompound of Formula (VI):R¹-A-V—B—R²  (VI)

wherein:

-   -   V is a 5-membered heteroaryl ring containing up to four        heteroatoms selected from O, N and S, optionally substituted by        C₁₋₄ alkyl;    -   A is —CH═CH— or (CH₂)_(n);    -   B is —CH═CH— or (CH₂)_(n), where one of the CH₂ groups may be        replaced by O, NR⁵, S(O)_(m), C(O) or C(O)NR¹²;    -   n is independently 0, 1, 2 or 3;    -   m is independently 0, 1 or 2;    -   R¹ is 3- or 4-pyridyl, 4- or 5-pyrimidinyl or 2-pyrazinyl, any        of which may be optionally substituted by one or more        substituents selected from halo, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,        C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₇ cycloalkyl, aryl, OR⁶, CN, NO₂,        S(O)_(m)R⁶, CON(R⁶)₂, N(R⁶)₂, NR¹⁰COR⁶, NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, a        4- to 7-membered heterocyclyl group or a 5- or 6-membered        heteroaryl group;    -   R² is 4- to 7-membered cycloalkyl substituted by R³, C(O)OR³,        C(O)R³ or S(O)₂R³, or 4- to 7-membered heterocyclyl, containing        one or two nitrogen atoms which is unsubstituted or substituted        by C(O)OR⁴, C(O)R³, S(O)₂R³, C(O)NHR⁴, P(O)(OR¹¹)₂ or a 5- or        6-membered nitrogen containing heteroaryl group;    -   R³ is C₃₋₈ alkyl, C₃₋₈ alkenyl or C₃₋₈ alkynyl, any of which may        be optionally substituted with up to 5 fluoro or chloro atoms,        and may contain a CH₂ group that may be replaced by O, or C₃₋₇        cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkylC₃₋₇        cycloalkyl, C₁₋₄ alkylaryl, C₁₋₄ alkylheterocyclyl or C₁₋₄        alkylheteroaryl, any of which may be optionally substituted with        one or more substituents selected from halo, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, OR⁶, CN, CO₂C₁₋₄ alkyl, N(R⁶)₂ and NO₂;

R⁴ is C₂₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, any of which may beoptionally substituted with up to 5 fluoro or chloro atoms, and maycontain a CH₂ group that may be replaced by O, or C₃₋₇ cycloalkyl, aryl,heterocyclyl, heteroaryl, C₁₋₄ alkylC₃₋₇ cycloalkyl, C₁₋₄ alkylaryl,C₁₋₄ alkylheterocyclyl or C₁₋₄ alkylheteroaryl, any of which may besubstituted with one or more substituents selected from halo, C₁₋₄alkyl, C₁₋₄ fluoroalkyl, OR⁶, CN, CO₂C₁₋₄ alkyl, N(R⁶)₂ and NO₂;

-   -   R⁵ is hydrogen, C(O)R⁷, S(O)₂R⁸, C₃₋₇ cycloalkyl or C₁₋₄ alkyl        optionally substituted by OR⁶, C₃₋₇ cycloalkyl, aryl,        heterocyclyl or heteroaryl, wherein the cyclic groups may be        substituted with one or more substituents selected from halo,        C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, OR⁶, CN, N(R⁶)₂ and NO₂;

R⁶ are independently hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl, aryl,heterocyclyl or heteroaryl, wherein the cyclic groups may be substitutedwith one or more substituents selected from halo, C₁₋₄ alkyl, C₁₋₄fluoroalkyl, OR⁹, CN, SO₂CH₃, N(R¹⁰)₂ and NO₂; or a group (N(R¹⁰)₂ mayform a 4- to 7-membered heterocyclic ring optionally containing afurther heteroatom selected from O and NR¹⁰;

-   -   R⁷ is hydrogen, C₁₋₄ alkyl, OR⁶, N(R⁶)₂, aryl or heteroaryl;    -   R⁸ is C₁₋₄ alkyl, C₁₋₄-fluoroalkyl, aryl or heteroaryl;    -   R⁹ is hydrogen, C₁₋₂ alkyl or C₁₋₂ fluoroalkyl;    -   R¹⁰ is hydrogen or C₁₋₄ alkyl;    -   R¹¹ is phenyl; and    -   R¹² is hydrogen, C₁₋₄ alkyl or C₃₋₇ cycloalkyl.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/GB2004/050046 include the following compoundsaccording to Formula (VI) (referred to herein as Group F1):4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidtert-butyl ester;3-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Pentylcyclohexylmethyl)-[1,2,4]oxadiazol-3-yl]pyridine;trans-2-Chloro-4-[5-(4-pentylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[5-(4-Pentylcyclohexane)-[1,2,4]oxadiazol-3-ylmethyl]pyridine;4-(3-Pyridin-4-ylmethyl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylicacid tert-butyl ester;trans-3-[5-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-3-ylmethyl]pyridine;4-[5-(4-Butylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;4-[5-(4-n-Propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[5-(4-Pentylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;4-[2-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)-ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;3-[5-(4-Propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;3-[5-(4-Butylcyclohexane)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine-2-carboxylicacid methylamide;trans-4-[5-(4-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine-2-carboxylicacid amide;trans-4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-3-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Methyl-3-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-6-methyl-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine-2-carbonitrile;trans-2-Chloro-3-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-6-methyl-3-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Methyl-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-3-Methyl-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2,6-Dichloro-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Chloro-6-methoxy-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-5-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]-2-[1,2,4]triazol-1-ylpyridine;2-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyrazine;4-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-5-[[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine-2-carbonitrile;trans-5-Chloro-2-methylsulfanyl-4-(3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyrimidine;trans-2-Fluoro-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Fluoro-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Imidazol-1-yl-5-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-2-Methyl-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-3-Methyl-4-[3-(4-pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]pyridine;trans-4-{2-[3-(4-Pentylcyclohexyl)-[1,2,4]oxadiazol-5-yl]vinyl}pyridine;4-(5-Pyridin-4-yl-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-3-yl-vinyl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-3-yl-vinyl)-[1,2,4]oxadiazol-3-yl]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-3-yl-vinyl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;(E)-4-[5-(2-Pyridin-4-yl-vinyl)-[1,2,4]oxadiazol-3-yl]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Pyridin-4-yl-ethyl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester;4-{5-[2-(2-Cyanopyridin-4-yl)ethyl]-[1,2,4]oxadiazol-3-yl}piperidine-1-carboxylicacid tert-butyl ester;4-(5-[2-(2-Cyanopyridin-4-yl)ethyl]-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-[2-(2-Cyanopyridin-4-yl)ethyl]-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidisobutyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acid2-methoxyethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidethyl ester;3,3-Dimethyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]butan-1-one;2-Cyclopentyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidin-1-yl]ethanone;4-{5-[1-(Butane-1-sulfonyl)piperidin-4-yl]-[1,2,4]oxadiazol-3-yl}pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidpropylamide;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidtert-butylamide;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid cyclopentyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid benzyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid isobutyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid ethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid cycloheptyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid methyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-methoxy-ethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid isopropyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 4-methoxy-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2,2,2-trichloroethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 4-chloro-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-ethyl-hexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid propyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid hexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid (1S,2R,5S)-2-isopropyl-5-methylcyclohexyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2,2-dimethylpropyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid naphthalen-1-yl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-methoxy-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 3-trifluoromethylphenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid prop-2-ynyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid but-2-ynyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid pentyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid p-tolyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 2-chloro-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid naphthalen-2-yl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1H-carboxylicacid 4-methoxycarbonyl-phenyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid 4-fluoro-phenyl ester;3-Methyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]-butan-1-one;Phenyl-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]methanone;1-[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]butan-1-one;2,2-Dimethyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]propan-1-one;Cyclopentyl-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]methanone;[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1]-yl-p-tolylmethanone;3,3-Dimethyl-1-[4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]butan-1-one;4-(5-[1-(Butane-1-sulfonyl)piperidin-4-yloxymethyl]-[1,2,4]oxadiazol-3-yl)pyridine;4-{5-[1-(Propane-1-sulfonyl)piperidin-4-yloxymethyl]-[1,2,4]oxadiazol-3-yl}pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid tert-butylamide;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid o-tolylamide;trans-4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acidpropyl ester;trans-4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acidbutyl ester;trans-4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-yl)cyclohexanecarboxylic acidisobutyl ester;trans-4-[5-(4-Propoxymethylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;trans-4-[5-(4-Butoxymethylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;cis-4-[5-(3-Butoxymethylcyclopentyl)-[1,2,4]oxadiazol-3-yl]pyridine;cis-4-[5-(3-Propoxymethylcyclopentyl)-[1,2,4]oxadiazol-3-yl]pyridine;cis-4-[5-(3-Butoxymethylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl;2-[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]pyrazine;2-[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]pyrimidine;(4-Pentylcyclohexyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;(4-Pentylcyclohexyl-methyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;4-[(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-{([5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethyl]amino}-piperidine-1-carboxylicacid tert-butyl ester;Methyl-(4-pentylcyclohexyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;Methyl-(4-pentylcyclohexylmethyl)-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amine;4-[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Ethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Propyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Cyclopropylmethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Butyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-{[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-{[Ethyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}-piperidine-1-carboxylicacid tert-butyl ester;4-{[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethyl]ethylamino}-piperidine-1-carboxylicacid tert-butyl ester;4-[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid cyclopentyl ester;4-{[Methyl-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]methyl}-piperidine-1-carboxylicacid 2,2,2-trichloroethyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxymethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethyl)piperazine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethylsulfanyl)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethanesulfonyl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Pyridin-4-yl-[1,3,4]oxadiazol-2-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester; 3-Pyridin-4-yl-[1,2,4]oxadiazole-5-carboxylicacid (4-pentylcyclohexyl)amide;[4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidin-1-yl]phosphonicacid diphenyl ester;4-(4-Pyridin-4-yl-thiazol-2-ylmethoxy)piperidine-1-carboxylic acidtert-butyl ester;4-(2-Pyridin-4-yl-thiazol-4-ylmethyl)piperidine-1-carboxylic acidtert-butyl ester;trans-4-[5-(4-Pentyl-cyclohexyl)-[1,3,4]thiadiazol-2-yl]pyridine;4-(5-Pyridin-4-yl-[1,3,4]thiadiazol-2-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Pyridin-4-yl-4H-[1,2,4]triazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[2-(5-Pyridin-4-yl-isoxazol-3-yl)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-(5-Pyridin-4-yl-isoxazol-3-ylmethoxy)piperidine-1-carboxylic acidtert-butyl ester;4-(5-Pyridin-4-yl-isoxazol-3-ylmethyl)piperidine-1-carboxylic acidtert-butyl ester;4-[2-(1-Methyl-5-pyridin-4-yl-1H-pyrazol-3-yl)ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[2-(2-Methyl-5-pyridin-4-yl-2H-pyrazol-3-yl)ethyl]-piperidine-1-carboxylicacid tert-butyl ester;(E)-4-{5-[2-(2-Cyanopyridin-4-yl)vinyl]-[1,2,4]oxadiazol-3-yl}piperidine-1-carboxylicacid tert-butyl ester;4-(5-[2-(2H-Tetrazol-5-yl)pyridine-4-yl]-[1,2,4]oxadiazol-3-ylmethoxy)-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid isopropyl ester; and4-[5-(2-Cyanopyridin-4-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid phenyl ester.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/US06/00567 (published as WO 2006/083491), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US06/00567 as a GPR119 agonist is acompound of Formula (VII):

-   -   wherein:    -   X is N or CR₈ wherein R₈ is H or halogen;    -   Y is NH or O;    -   Z is CH or N;    -   R₁ is carbo-C₁₋₆-alkoxy, oxadiazolyl or pyrimidinyl wherein said        carbo-C₁₋₆-alkoxy, oxadiazolyl and pyrimidinyl are each        optionally substituted with 1 or 2 substituents selected        independently from the group consisting of C₁₋₄ alkyl, C₁₋₄        alkoxy and C₃₋₅ cycloalkyl;    -   R₂ is H or C₁₋₄ alkyl;    -   R₃ is C₁₋₄ alkoxy, O—C₂₋₄ alkynyl or hydroxyl;    -   R₄ is selected from the group consisting of H, C₁₋₄ alkoxy, C₁₋₄        alkyl, C₂₋₄ alkynyl and halogen;    -   R₅ is selected from the group consisting of C₁₋₄        acylsulfonamide, C₁₋₄ alkoxy, C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄        alkylsulfonyl, C₁₋₄ alkylthio, cyano, heterocyclyl,        di-C₁₋₄-dialkylamino and sulfonamide, wherein said C₁₋₄ alkoxy,        C₁₋₄ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio,        di-C₁₋₄-dialkylamino and heterocyclyl are each optionally        substituted with 1 or 2 substituents selected independently from        the group consisting of C₂₋₄ alkynyl, C₁₋₄ alkoxy, C₁₋₄        alkylcarboxamide, C₁₋₄ alkylsulfonyl, C₃₋₅ cycloalkyl, C-s        cycloalkyloxy, di-C₁₋₄-alkylcarboxamide, hydroxyl and        phosphonooxy, wherein said C₁₋₄ alkylcarboxamide is optionally        substituted with hydroxyl; or    -   R₅ is a group of Formula (VIIA):

-   -   wherein “m”, “n” and “q” are each independently 0, 1, 2 or 3;        “r” is 0, 1 or 2; and “t” is 0 or 1;    -   R₆ is H or halogen; and    -   R₇ is H or C₁₋₄ alkyl.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US06/00567 include the following compounds accordingto Formula (VII) (referred to herein as Group G1):4-[6-(4-Methanesulfonyl-2-methoxy-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[6-(2-methoxy-ethyl)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid 1-cyclopropyl-ethyl ester;4-[6-(2-Fluoro-4-methanesulfonyl-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(4-Cyano-2-fluoro-phenylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[6-(2-methoxy-ethylamino)-2-methyl-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(3-Hydroxy-propyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[2-methyl-6-(3-phosphonooxy-propyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethylamino)-2-methoxy-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Dimethylcarbamoylmethyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(6-{2-Fluoro-4-[(2-hydroxy-ethylcarbamoyl)-methyl]-phenylamino}-5-methoxy-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Methanesulfonyl-ethylamino)-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[2-Fluoro-4-(2-hydroxy-ethylsulfanyl)-phenylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2,3-Dihydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2,3-Dihydroxy-propylamino)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[2-methyl-6-(2-phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(3-Hydroxy-propoxy)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-{5-Methoxy-6-[2-methyl-6-(3-phosphonooxy-propoxy)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US06/00567 include the following compounds accordingto Formula (VII) (referred to herein as Group G2):4-[2-(2-Fluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-hydroxy-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Fluoro-2-(2-fluoro-4-methanesulfonyl-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Ethyl-4-(2-methanesulfonyl-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-2-methyl-piperidine-1-carboxylicacid isopropyl ester;4-{5-Fluoro-2-[6-(2-hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-methanesulfonyl-ethyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-[6-(2-Hydroxy-ethylamino)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[2-(4-Cyano-2-fluoro-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Chloro-4-cyano-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methoxy-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Hydroxy-butyl)-2-methoxy-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-hydroxy-ethoxy)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Ethoxy-2-[2-fluoro-4-(2-phosphonooxy-ethyl)-phenylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[3-Methoxy-2-(2-methoxy-4-propionylsulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2,5-Difluoro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;(2-Fluoro-4-methanesulfonyl-phenyl)-{4-[1-(5-isopropyl-[1,2,4]oxadiazol-3-yl)-piperidin-4-yloxy]-3-methoxy-pyridin-2-yl}-amine;(2-Fluoro-4-methanesulfonyl-phenyl)-(3-methoxy-4-[1-(5-methoxy-pyrimidin-2-yl)-piperidin-4-yloxy]-pyridin-2-yl)-amine;4-{2-[6-(2-Cyclopropoxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Chloro-4-methanesulfonyl-phenylamino)-5-fluoro-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[3-Ethoxy-2-(4-methanesulfonyl-2-methoxy-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(5-Fluoro-2-methyl-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Fluoro-4-methanesulfonyl-phenylamino)-3-hydroxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[2-(2-Chloro-4-propoxy-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Methanesulfonyl-ethylamino)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-(2-{6-[(2-Methanesulfonyl-ethyl)-methyl-amino]-2-methyl-pyridin-3-ylamino}-3-methoxy-pyridin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Methanesulfonyl-pyrrolidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(3-Methanesulfonyl-6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-ylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Methanesulfonyl-azetidin-1-yl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[3-Ethynyloxy-2-(2-fluoro-4-methanesulfonyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-phosphonooxy-ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[2-(4-Ethanesulfonyl-2-fluoro-phenylamino)-3-methoxy-pyridin-4-yloxy]-piperidine-1-carboxylicacid sec-butyl ester;4-{2-[6-(2,3-Dihydroxy-propylamino)-4-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethylsulfanyl)-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(2-hydroxy-ethanesulfonyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Hydroxy-propoxy)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(3-phosphonooxy-propoxy)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[3-Methoxy-2-(2-methoxy-4-sulfamoyl-phenylamino)-pyridin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-{2-[2-Fluoro-4-(3-phosphonooxy-propyl)-phenylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(2-Hydroxy-ethyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{3-Methoxy-2-[2-methyl-6-(2-phosphonooxy-ethyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{2-[6-(3-Hydroxy-propyl)-2-methyl-pyridin-3-ylamino]-3-methoxy-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester; and4-{3-Methoxy-2-[2-methyl-6-(3-phosphonooxy-propyl)-pyridin-3-ylamino]-pyridin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/US06/00567 include the following compounds accordingto Formula (VII) (referred to herein as Group G3):4-[6-(2,6-Dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Methoxy-6-(2-methyl-6-propylsulfanyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-(5-Methoxy-6-[2-methyl-6-(propane-1-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy)-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Ethanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Isopropylsulfanyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidin-1-carboxylicacid isopropyl ester;4-{5-Methoxy-6-[2-methyl-6-(propane-2-sulfonyl)-pyridin-3-ylamino]-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-{6-[6-(2-Hydroxy-ethanesulfonyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl ester;4-[5-Hydroxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Ethoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[5-Isopropoxy-6-(6-methanesulfonyl-2-methyl-pyridin-3-ylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-propoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid 1-ethyl-propyl ester;4-[6-(6-Methanesulfonyl-2-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid sec-butyl ester;4-[6-(6-Cyano-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;4-[6-(6-Hydroxymethyl-4-methyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester;{6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl-2-methyl-pyridin-3-yl)-amine;4-[6-(6-Methanesulfonyl-2,4-dimethyl-pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester; and4-{6-[6-(1-Methanesulfonyl-1-methyl-ethyl)-2-methyl-pyridin-3-ylamino]-5-methoxy-pyrimidin-4-yloxy}-piperidine-1-carboxylicacid isopropyl.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2005/050264 (published as WO 2006/067531), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/GB2005/050264 as a GPR119 agonist is acompound of Formula (VIII):

wherein:

-   -   one of A and B is nitrogen and the other is CR¹;    -   W and Y are independently a bond, an unbranched or a branched        C₁₋₃ alkylene or an unbranched or a branched C₂₋₃ alkenylene;    -   X is selected from CH₂, O, S, CH(OH), CH(halogen), C(O), C(O)O,        C(O)S, SC(O), C(O)CH₂S, C(O)CH₂C(OH), C(O)CH₂C(O), OC(O), NR⁵,        CH(NR⁵R⁵⁵), C(O)NR², S(O) and S(O)₂;    -   G is CHR³, N—C(O)OR⁴, N—C(O)NR⁴R⁵, N—C₁₋₄alkylene-C(O)OR⁴,        N—C(O)C(O)OR⁴, N—S(O)₂R⁴, N—C(O)R⁴ or N—P(O)(O-Ph)₂; or        N-heterocyclyl or N-heteroaryl, either of which may optionally        be substituted by one or two groups selected from C₁₋₄alkyl,        C₁₋₄alkoxy or halogen;    -   R¹ is hydrogen, halogen, cyano, C(O)NH₂, C₁₋₄alkyl,        SO₂C₁₋₄alkyl, SOC₁₋₄alkyl or SC₁₋₄alkyl;

R² is hydrogen or C₁₋₄alkyl;

R³ is C₃₋₆alkyl;

R⁴ is C₁₋₈alkyl, C₂₋₈alkenyl or C₂₋₈alkynyl, any of which may beoptionally substituted by one or more halo atoms, NR⁵R⁵⁵, OR⁵, C(O)OR⁵,OC(O)R⁵ or cyano, and may contain a CH₂ group that is replaced by O orS; or a C₃₋₇cycloalkyl, aryl, heterocyclyl, heteroaryl,C₁₋₄alkyleneC₃₋₇cycloalkyl, C₁₋₄alkylenearyl, C₁₋₄alkyleneheterocyclylor C₁₋₄alkyleneheteroaryl, any of which may be substituted with one ormore substitutents selected from halo, C₁₋₄alkyl, C₁₋₄fluoroalkyl, OR⁵,CN, NR⁵R⁵⁵, SO₂Me, NO₂ or C(O)OR⁵;

R⁵ and R⁵⁵ are independently hydrogen or C₁₋₄alkyl; or taken together R⁵and R⁵⁵ may form a 5 or 6 membered heterocyclic ring;

-   -   R⁶ is hydrogen, halogen, CN, C₁₋₄alkyl, C₁₋₄alkoxy, ethynyl,        C(O)NR⁷R⁷⁷ or C₁₋₄alkyleneS(O)_(f);    -   R⁷ and R⁷⁷ are independently hydrogen or C₁₋₄alkyl; or taken        together R⁷ and R⁷⁷ may form a 5 or 6 membered heterocyclic        ring;    -   R⁸ is hydrogen, halogen, CN, C₁₋₄alkyl or C₁₋₄alkoxy;    -   R¹¹ is hydrogen or hydroxy;    -   d is 0, 1, 2 or 3;    -   e is 1, 2, 3, 4 or 5;    -   with the proviso that d+e is 2, 3, 4 or 5; and    -   f is 0, 1 or 2.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/GB2005/050264 include the following compoundsaccording to Formula (VIII) (referred to herein as Group H1):4-(3-Pyridin-4-ylpropylsulfanylcarbonyl)piperidine-1-carboxylic acidtert-butyl ester; 4-Pentylcyclohexane carbothioic acidS-(3-pyridin-4-ylpropyl) ester;4-(2-Pyridin-4-ylethylsulfanylcarbonyl)piperidine-1-carboxylic acidtert-butyl ester; 4-Pentylcyclohexane carbothioic acidS-(2-pyridin-4-ylethyl) ester;4-(Pyridine-4-carbonylsulfanyl)piperidine-1-carboxylic acid tert-butylester; (E)-4-(3-Pyridin-4-ylacryloylsulfanyl)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Pyridin-4-ylpropionylsulfanyl)piperidine-1-carboxylic acidtert-butyl ester;4-(Pyridine-4-carbonylsulfanylmethyl)piperidine-1-carboxylic acidtert-butyl ester;4-(3-Pyridin-4-ylpropionylsulfanylmethyl)piperidine-1-carboxylic acidtert-butyl ester; 4-(2-Pyridin-4-ylacetoxymethyl)piperidine-1-carboxylicacid tert-butyl ester; 4-(2-Pyridin-4-ylacetoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[3-(2-Pyridin-4-ylacetoxy)propyl]piperidine-1-carboxylic acidtert-butyl ester; Isonicotinic acid3-(1-tert-butoxycarbonylpiperidin-4-yl)propyl ester;(E)-4-(3-Pyridin-4-ylacryloyloxymethyl)piperidine-1-carboxylic acidtert-butyl ester;(E)-4-(3-Pyridin-4-ylacryloyloxy)piperidine-1-carboxylic acid tert-butylester;(E)-4-[3-(3-Pyridin-4-ylacryloyloxy)propyl]piperidine-1-carboxylic acidtert-butyl ester;4-(2-Pyridin-4-ylethoxycarbonylmethyl)piperidine-1-carboxylic acidtert-butyl ester; Piperidine-1,4-dicarboxylic acid 1-tert-butyl ester4-(2-pyridin-4-ylethyl) ester; Piperidine-1,4-dicarboxylic acid1-tert-butyl ester 4-(3-pyridin-4-ylpropyl) ester;(E)-4-[Methyl(3-pyridin-4-ylacryloyl)amino]piperidine-1-carboxylic acidtert-butyl ester;4-(2-[Methyl(pyridine-4-carbonyl)amino]ethyl)piperidine-1-carboxylicacid tert-butyl ester;4-[Methyl(pyridine-4-carbonyl)amino]piperidine-1-carboxylic acidtert-butyl ester;4-{2-[Methyl(2-pyridin-4-ylacetyl)amino]ethyl}piperidine-1-carboxylicacid tert-butyl ester;4-{2-[Methyl(3-pyridin-4-ylacryloyl)amino]ethyl}piperidine-1-carboxylicacid tert-butyl ester;4-{[Methyl-(3-pyridin-4-ylacryloyl)amino]methyl}piperidine-1-carboxylicacid tert-butyl ester;4-(2-Pyridin-4-ylethylsulfanylmethyl)piperidine-1-carboxylic acidtert-butyl ester; 4-(2-Pyridin-4-ylethylsulfanyl)piperidine-1-carboxylicacid tert-butyl ester;4-[2-(2-Pyridin-4-ylethylsulfanyl)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-(3-Pyridin-4-ylpropylsulfanylmethyl)piperidine-1-carboxylic acidtert-butyl ester;4-(3-Pyridin-4-ylpropylsulfanyl)piperidine-1-carboxylic acid tert-butylester; 4-[2-(3-Pyridin-4-ylpropylsulfanyl)ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-(2-Pyridin-4-ylethoxymethyl)piperidine-1-carboxylic acid tert-butylester; 4-(3-Pyridin-4-ylpropoxymethyl)piperidine-1-carboxylic acidtert-butyl ester;4-[2-(3-Pyridin-4-ylpropoxy)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-[2-(2-Pyridin-4-ylethoxy)ethyl]piperidine-1-carboxylic acid tert-butylester; 4-[3-(2-Cyanopyridin-4-yl)propoxymethyl]piperidine-1-carboxylicacid tert-butyl ester;4-{2-[3-(2-Cyanopyridin-4-yl)propoxy]ethyl}piperidine-1-carboxylic acidtert-butyl ester;4-[3-Pyridin-4-ylmethoxy)propyl]piperidine-1-carboxylic acid tert-butylester; 4-[2-(2-Bromopyridin-4-ylmethoxy)ethyl]piperidine-1-carboxylicacid tert-butyl ester; 4-(3-Pyridin-4-ylpropoxy)piperidine-1-carboxylicacid tert-butyl ester;4-[3-(pyridin-4-yloxy)propyl]piperidine-1-carboxylic acid tert-butylester; 4-[2-(Pyridin-4-ylmethoxy)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-(2-Oxo-2-pyridin-4-ylethylsulfanylmethyl)piperidine-1-carboxylic acidtert-butyl ester;4-(3-Pyridin-4-ylpropane-1-sulfonyl)piperidine-1-carboxylic acidtert-butyl ester;4-(3-Pyridin-4-ylpropane-1-sulfinyl)piperidine-1-carboxylic acidtert-butyl ester;4-(3-Pyridin-4-ylpropane-1-sulfonylmethyl)piperidine-1-carboxylic acidten-butyl ester;4-(3-Pyridin-4-ylpropane-1-sulfinylmethyl)piperidine-1-carboxylic acidtert-butyl ester;4-[2-(3-Pyridin-4-ylpropane-1-sulfonyl)ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[2-(3-Pyridin-4-ylpropane-1-sulfinyl)ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-(2-Pyridin-4-ylethanesulfonylmethyl)piperidine-1-carboxylic acidtert-butyl ester;(E)-4-(2-Oxo-4-pyridin-4-ylbut-3-enyl)piperidine-1-carboxylic acidtert-butyl ester;(E)-4-(4-Pyridin-4-ylbut-3-enyl)piperidine-1-carboxylic acid tert-butylester; (Z)-4-(4-Pyridin-4-ylbut-3-enyl)piperidine-1-carboxylic acidtert-butyl ester; (E)-4-(3-Pyridin-4-ylallyl)piperidine-1-carboxylicacid tert-butyl ester;(Z)-4-(3-Pyridin-4-ylallyl)piperidine-1-carboxylic acid tert-butylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid tert-butylester; 4-(3-Pyridin-4-ylpropyl)piperidine-1-carboxylic acid tert-butylester; 4-(2-Methyl-3-pyridin-4-ylpropyl)piperidine-1-carboxylic acidtert-butyl ester;(E)-4-[4-(2-Cyanopyridin-4-yl)but-3-enyl]piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)butyl]piperidine-1-carboxylic acid tert-butylester; 4-[3-(2-Cyanopyridin-4-yl)propyl]piperidine-1-carboxylic acidtert-butyl ester;4-[2-(2-Cyanopyridin-4-ylmethoxy)ethyl]piperidine-1-carboxylic acidtert-butyl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butylamide; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butylmethylamide; 4-(4-Pyridin-4-yl-butyl)piperidine-1-carboxylicacid 2,2,2-trichloroethyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid isobutyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid 4-methoxyphenylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid2,2-dimethylpropyl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylicacid phenyl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acidcyclopentyl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid2-chlorobenzyl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylicacid p-tolyl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acidpropyl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid hexylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid prop-2-ynylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acidnaphthalen-1-yl ester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylicacid 4-fluorophenyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid4-methoxycarbonylphenyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid 4-nitrophenyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid isopropyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid 4-chlorophenylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid3-trifluoromethylphenyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid 2-chlorophenylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid2-methoxyphenyl ester; 4-(4-Pyridin-4-yl-butyl)piperidine-1-carboxylicacid but-2-ynyl ester, 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylicacid naphthalen-2-yl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid pentyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid o-tolyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid2-cyano-1,1-dimethylethyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid 2,2,2-trifluoroethylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid cyclobutylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid cyclohexylester; 4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acid2-methylsufanylethyl ester;4-(4-Pyridin-4-ylbutyl)piperidine-1-carboxylic acidtetrahydrofuran-2-ylmethyl ester;2-[4-(4-Pyridin-4-ylbutyl)piperidin-1-yl]propionic acid ethyl ester;[4-(4-Pyridin-4-ylbutyl)piperidin-1-yl]acetic acid ethyl ester;[4-(4-Pyridin-4-ylbutyl)piperidin-1-yl]acetic acid tert-butyl ester;Oxo-[4-(4-pyridin-4-ylbutyl)piperidin-1-yl]acetic acid methyl ester;2-[4-(4-Pyridin-4-ylbutyl)piperidin-1-yl]pyrimidine;4-(4-Pyridin-4-ylbutyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;4-(2,4-Dioxo-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acid tert-butylester; 4-(3,5-Dioxo-5-pyridin-4-yl-pentyl)piperidine-1-carboxylic acidtert-butyl ester;4-[1-(2-Cyanopyridin-4-yl)vinyloxycarbonylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-(2-Hydroxy-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acid tert-butylester; 4-(2-Hydroxy-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butyl ester;4-(2-Hydroxy-4-oxo-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)-2-hydroxy-4-oxobutyl]piperidine-1-carboxylicacid tert-butyl ester;4-(1-Hydroxy-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acid tert-butylester; (Z)-4-(4-Oxo-4-pyridin-4-ylbut-2-enyl)piperidine-1-carboxylicacid tert-butyl ester;4-(4-Oxo-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acid tert-butylester; 4-(4-hydroxy-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)-2-hydroxybutyl]piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)-4-hydroxybutyl]piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)-1-hydroxybutyl]piperidine-1-carboxylic acidtert-butyl ester; 4-(2-Oxo-4-pyridin-4-ylbutyl)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Oxo-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acid tert-butylester; 4-(4-Pyridin-4-yl-butyryl)piperidine-1-carboxylic acid tert-butylester; 4-[4-(2-Cyanopyridin-4-yl)-2-oxobutyl]piperidine-1-carboxylicacid tert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)butyryl]piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)butyryl]piperidine-1-carboxylic acidtert-butyl ester;4-(3-Methylamino-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butyl ester;4-(1-Methylamino-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)-4-methylaminobutyl]piperidine-1-carboxylicacid tert-butyl ester;4-[4-(2-Cyano-pyridin-4-yl)-2-methylamino-butyl]piperidine-1-carboxylicacid tert-butyl ester;4-(1-Dimethylamino-4-pyridin-4-ylbutyl)piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)-4-dimethylaminobutyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[4-(2-Cyanopyridin-4-yl)-2-dimethylaminobutyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[2-(2-Carbamoylpyridin-4-ylmethoxy)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-[2-(2-Ethynylpyridin-4-ylmethoxy)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-[(E)-4-(2-Methylpyridin-4-yl)but-3-enyl]piperidine-1-carboxylic acidter-butyl ester;4-[(Z)-4-(2-Methylpyridin-4-yl)but-3-enyl]piperidine-1-carboxylic acidtert-butyl ester;4-[4-(2-Methylpyridin-4-yl)butyl]piperidine-1-carboxylic acid tert-butylester;4-Hydroxy-4-[4-(2-methylpyridin-4-yl)butyl]piperidine-1-carboxylic acidter-butyl ester.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2005/050265 (published as WO 2006/067532), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/GB2005/050265 as a GPR119 agonist is acompound of Formula (IX):

or an N-oxide thereof,

wherein:

-   -   one of E¹ and E² is N and the other is N or C-G²;    -   the dashed line together with the solid line forms an optional        double bond;    -   when the dashed line together with the solid line forms a double        bond E³ is CR⁸ or N, and when it is a single bond E³ is CHR⁸, O        or NR²;    -   T is O, S, NR², (CH₂)₂, or E⁴=E⁵, where E⁴ and E⁵ are        independently CH or N;    -   B is a bond, —CH₂═CH₂— or (CH₂)_(j);    -   j is 1, 2 or 3;    -   Q is a bond, C(O)S, or a 5- or 6-membered heteroaromatic ring;    -   A is (CH₂)_(n), where one CH₂ group may be replaced by O, S,        C(O), CH(OH)CH(Hal) CH(NR²R³), S(O), S(O)₂ or NR³; two CH₂        groups may be replaced by CH═CH, C(O)O, C(O)S, SC(O), C(O)NR² or        OC(O); or three CH₂ groups may be replaced by C(O)CH₂S,        C(O)CH₂C(OH) or C(O)CH₂C(O);    -   n is 0, 1, 2, 3, 4, 5, or 6;    -   G¹ and G² are independently hydrogen, halogen, CF₃, C₁₋₄alkoxy,        NR⁴R⁴⁴, SO₂C₁₋₄alkyl, SOC₁₋₄alkyl, SC₁₋₄alkyl or cyano; or        C₁₋₄alkyl, C₂₋₄alkenyl, or C₂₋₄alkynyl, optionally substituted        by hydroxy, NR⁴R⁴⁴, oxo or C₁₋₄alkoxy;    -   D represents CHR⁹ or NR¹;    -   R¹ is C(O)OR⁵, C(O)R⁵, S(O)₂R⁵, C(O)NR⁵R¹⁰, C(O)NR⁵R⁵⁵,        C₁₋₄alkylene-C(O)OR⁵, C(O)C(O)OR⁵, S(O)₂R⁵, C(O)R⁵ or        P(O)(O-Ph)₂; or heterocyclyl or heteroaryl, either of which may        optionally be substituted by one or two groups selected from        C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkyl-OH, halogen, C₁₋₄-fluoroalkyl,        heterocyclyl, C(O)OC₁₋₄alkyl;    -   R² and R³ are independently hydrogen or C₁₋₄alkyl;    -   R⁴ and R⁴⁴ are independently hydrogen, C₁₋₄alkyl,        C₃₋₇cycloalkyl, or aryl, which may optionally be substituted        with 1 or 2 substituents selected from halo, C₁₋₄alkyl, CF₃,        C₁₋₄alkoxy, cyano, and S(O)₂Me; or, taken together, R⁴ and R⁴⁴        may form a 5- or 6-membered heterocyclic ring;    -   R⁵ and R⁵⁵ are independently C₁₋₈alkyl, C₂₋₈alkenyl or        C₂₋₈alkynyl, any of which may be optionally substituted by one        or more halo atoms, NR⁶R⁶⁶, OR⁶, C(O)OR⁶, OC(O)R⁶ or cyano, and        may contain a CH₂ group that is replaced by O or S; or a        C₃₋₇cycloalkyl, aryl, heterocyclyl, heteroaryl,        C₁₋₄alkyleneC₃₋₇cycloalkyl, C₁₋₄alkylenearyl,        C₁₋₄alkyleneheterocyclyl or C₁₋₄alkyleneheteroaryl, any of which        may be substituted with one or more substituents selected from        halo, C₁₋₄alkyl, C₁₋₄fluoroalkyl, OR⁷, CN, NR⁷R⁷⁷, SO₂Me, NO₂ or        C(O)OR⁷;    -   R⁶, R⁶⁶, R⁷, and R⁷⁷ each independently are hydrogen or        C₁₋₄alkyl; or, taken together, R⁶ and R⁶⁶ or R⁷ and R⁷⁷ may form        a 5- or 6-membered heterocyclic ring;    -   R⁸ is hydrogen, hydroxy, C₁₋₄alkoxy or benzyloxy;    -   R⁹ is C₃₋₆alkyl    -   R¹⁰ is hydrogen or C₁₋₄alkyl;    -   R¹¹ is hydrogen or hydroxy;    -   x is 0, 1, 2 or 3; and    -   y is 1, 2, 3, 4 or 5;    -   with the proviso that x+y is 2, 3, 4 or 5.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/GB2005/050265 include the following compoundsaccording to Formula (IX) (referred to herein as Group I1):4-(Furo[3,2-c]pyridine-2-carbonylsulfanyl)piperidine-1-carboxylic acidtert-butyl ester;4-([1,6]Naphthyridine-2-carbonylsulfany)-piperidine-1-carboxylic acidtert-butyl ester;4-([1,7]Naphthyridine-3-carbonylsulfanyl)-piperidine-1-carboxylic acidtert-butyl ester;4-(6-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonylsulfanyl)-piperidine-1-carboxylicacid tert-butyl ester;4-(1H-Pyrrolo[2,3-c]pyridine-2-carbonylsulfanyl)-piperidine-1-carboxylicacid tert-butyl ester;4-(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonylsulfanyl)-piperidine-1-carboxylicacid tert-butyl ester;4-([1,6]Naphthyridine-2-carbonylsulfanylmethyl)-piperidine-1-carboxylicacid tert-butyl ester;4-(1H-Pyrrolo[2,3-c]pyridine-2-carbonylsulfanylmethyl)-piperidine-1-carboxylicacid tert-butyl ester;4-(Furo[3,2-c]pyridine-2-carbonylsulfanylmethyl)-piperidine-1-carboxylicacid tert-butyl ester;4-(6-Chloro-1H-pyrrolo[3,2-c]pyridine-2-carbonylsulfanylmethyl)-piperidine-1-carboxylicacid tert-butyl ester;4-(5-Chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonylsulfanylmethyl)-piperidine-1-carboxylicacid tert-butyl ester;4-([1,7]Naphthyridine-3-carbonylsulfanylmethyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[2-(Furo[3,2-c]pyridin-2-ylmethoxy)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-(Furo[3,2-c]pyridin-2-ylmethoxy)piperidine-1-carboxylic acidtert-butyl ester;4-(Furo[3,2-c]pyridin-2-ylmethoxymethyl)-piperidine-1-carboxylic acidtert-butyl ester;4-[3-(Furo[3,2-c]pyridin-2-ylmethoxy)propyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[4-(Furo[3,2-c]pyridin-2-ylmethoxy)butyl]-piperidine-1-carboxylic acidtert-butyl ester;4-(2-Furo[3,2-c]pyridin-2-ylethyl)piperidine-1-carboxylic acidtert-butyl ester;4-(3-Furo[3,2-c]pyridin-2-ylpropyl)piperidine-1-carboxylic acidtert-butyl ester;4-(2-Furo[2,3-c]pyridin-2-ylethyl)piperidine-1-carboxylic acidtert-butyl ester;4-(2-Oxazolo[4,5-c]pyridin-2-yl-2-oxo-ethyl)piperidine-1-carboxylic acidtert-butyl ester;4-(2-Chloro-2-oxazolo[4,5-c]pyridin-2-ylethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(2-Oxazolo[4,5-c]pyridin-2-yl-ethyl)piperidine-1-carboxylic acidtert-butyl ester; 4-[5-(4-Hydroxymethylfuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Methoxymethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Dimethylaminomethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Pyrrolidin-1-ylmethylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Formylfuro[3,2-c]pyridine-2-yl)-[1,2,4]oxadiazole-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-([(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)amino]methyl)-piperidine-1-carboxylicacid tert-butyl ester;4-[5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1-carboxylicacid tert-butyl ester;4-[Ethyl(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)amino]-piperidine-1-carboxylicacid tert-butyl ester;4-[(5-Furo[3,2-c]pyridine-2-yl-[1,2,4]oxadiazol-3-ylmethyl)propylamino]-piperidine-1-carboxylicacid tert-butyl ester;4-(5-Furo[3,2-c]pyridine-2-yl-[1,2,4]oxadiazol-3-ylmethyl)methylamino)-piperidine-1-carboxylicacid tert-butyl ester;4-[(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethyl)methylamino]-piperidine-1-carboxylicacid tert-butyl ester;4-[Ethyl(3-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethyl)amino]-piperidine-1-carboxylicacid tert-butyl ester;4-(5-Thieno[2,3-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Thieno[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Thieno[2,3-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Thieno[2,3-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Thieno[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Thieno[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylicacid tert-butyl ester;4-(5-[1,7]Naphthyridin-3-yl-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-[1,7]Naphthyridin-3-yl-[1,2,4]oxadiazol-3-yl)-piperidine-1-carboxylicacid tert-butyl ester;4-(5-[1,7]Naphthyridin-3-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;4-[5-(1-Methyl-1H-pyrrolo[2,3-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(1H-Pyrrolo[2,3-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(1H-Pyrrolo[2,3-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-(5-Furo[2,3-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;4-(5-Furo[2,3-c]pyridin-2-yl-[1,2,4]oxadiazol-3-yl)piperidine-1-carboxylicacid tert-butyl ester;4-[5-(1H-Pyrrolo[2,3-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(7,8-Dihydro-isoquinolin-6-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Chlorofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Chlorofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethyl)piperidine-1-carboxylicacid tert-butyl ester;4-(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester;(3S)-3-(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethoxy)pyrrolidine-1-carboxylicacid tert-butyl ester;(3R)-3-(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethoxy)pyrrolidine-1-carboxylicacid tert-butyl ester;3-(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-ylmethoxy)azetidine-1-carboxylicacid tert-butyl ester;3-[2-(3-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-5-yl)-ethoxy]azetidine-1-carboxylicacid tert-butyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid propyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid isopropyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid ethyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid isobutyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid cyclopropylmethyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid 2-methoxycarbonyl-2-methylpropyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid (S)-sec-butyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid cyclobutyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid 1-methoxycarbonyl-1-methylethyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid 1-methyl-cyclobutyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid (R)-tetrahydrofuran-2-ylmethyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid 2-ethoxy-ethyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid 1-methyl-cyclopropyl ester;2-[3-(1-Pyrimidin-2-ylpiperidin-4-ylmethyl)-[1,2,4]oxadiazol-5-yl]furo[3,2-c]pyridine;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid 1-carboxy-1-methylethyl ester;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidine-1-carboxylicacid 2-carboxy-2-methylpropyl ester;4-[5-(5-Oxyfuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[2-(5-Oxyfuro[3,2-c]pyridin-2-yl)ethyl]piperidine-1-carboxylic acidtert-butyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[2-(4-Cyanofuro[3,2-c]pyridin-2-ylmethoxy)-ethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[2-(4-Cyanofuro[3,2-c]pyridin-2-yl)ethyl]-piperidine-1-carboxylic acidtert-butyl ester;4-[5-(7-Cyanofuro[2,3-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-[(5-(4-Cyanothieno[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid propyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid isopropyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid isobutyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid ethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid cyclobutyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tetrahydropyran-4-yl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid (R)-sec-butyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tetrahydrofuran-2-ylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid (R)-tetrahydrofuran-2-ylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid (R)-tetrahydrofuran-3-yl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tetrahydrothiopyran-4-yl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 1-methoxycarbonyl-1-methylethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid methoxycarbonylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid cyclopropylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 3-ethoxy-propyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid (S)-sec-butyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 3-methyl-oxetan-3-ylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 2-ethoxy-ethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]-oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 2-methoxy-1-methylethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tetrahydrofuran-3-ylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid (S)-tetrahydrofuran-3-yl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tetrahydropyran-2-ylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 1-methyl-cyclopropyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 1-methyl-cyclobutyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 1-cyclopropylethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 1-methyl-cyclopropylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 2-methyl-cyclopropylmethyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 3-methoxypropyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 3-acetoxypropyl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid oxetan-3-yl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 1-oxo-hexahydro-1λ⁴-thiopyran-4-yl ester;4-[5-(4-Cyanofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid 1,1-dioxo-hexahydro-1λ⁶-thiopyran-4-yl ester;4-[5-(3-Benzyloxyfuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(3-Hydroxyfuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]-piperidine-1-carboxylicacid tert-butyl ester;4-[5-(4-Methylfuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-[5-(7-Iodofuro[3,2-c]pyridin-2-yl)-[1,2,4]oxadiazol-3-ylmethyl]piperidine-1-carboxylicacid tert-butyl ester;4-Chloro-2-[3-(1-pyrimidin-2-ylpiperidin-4-yloxymethyl)-[1,2,4]oxadiazol-5-yl]furo[3,2-c]pyridine;2-(3-((1-(3-Methoxypyridin-2-yl)piperidine-4-yl)methyl)-[1,2,4]-oxadiazol-5-yl)furo[3,2-c]pyridine;Ethyl6-(4-((5-(furo[3,2-c]pyridin-2-yl)-[1,2,4]-oxadiazol-3-yl)methyl)piperidin-1-yl)nicotinate;2-{3-[1-(4,6-Dimethyl-pyrimidin-2-yl)piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}-furo[3,2-c]pyridine;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-3′-carboxylicacid ethyl ester;2-[4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidin-1-yl]-quinoline;1-[4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidin-1-yl]isoquinoline;2-[3-(1-Pyrazin-2-yl-piperidin-4-ylmethyl)-[1,2,4]oxadiazol-5-yl]-furo[3,2-c]pyridine;2-{3-[1-(4-Methoxy-pyrimidin-2-yl)-piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}-furo[3,2-c]pyridine;[4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-methanol;2-{3-[1-(5-Ethyl-pyrimidin-2-yl)-piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}-furo[3,2-c]pyridine;2′-Chloro-4-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl;4′-Chloro-4-(5-furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;2-[4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)piperidin-1-yl]-quinoxaline;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-6′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;2-{3-[1-(6-Methyl-pyridazin-3-yl)piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}furo[3,2-c]pyridine;[4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4′-yl]-methanol;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-5′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-4′-methyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;2-{3-[1-(5-Propyl-pyrimidin-2-yl)-piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}-furo[3,2-c]pyridine;2-{3-[1-(1H-Benzoimidazol-2-yl)-piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}furo[3,2-c]pyridine;4-(5-Furo[3,2-c]pyridin-2-yl-[1,2,4]oxadiazol-3-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl;2-{3-[1-(Furo[3,2-c]pyridin-4-yl)piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}-furo[3,2-c]pyridine;2-{3-[1-(2-Chloro-pyrimidin-4-yl)piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}furo[3,2-c]pyridine;2-{3-[1-(4-Morpholin-4-yl-pyrimidin-2-yl)-piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}-furo[3,2-c]pyridine;2-{3-[1-(4-Trifluoromethyl-phenyl)-piperidin-4-ylmethyl]-[1,2,4]oxadiazol-5-yl}furo[3,2-c]pyridine.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2005/050266 (published as WO 2006/070208), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/GB2005/050266 as a GPR119 agonist is acompound of Formula (X):R¹-A-V—B—R²  (X)

wherein:

-   -   V is phenyl or a 6-membered heteroaryl ring containing up to        three N atoms;    -   A is —CH═CH— or (CH₂)_(n);    -   B is —CH═CH— or (CH₂)_(n), where one of the CH₂ groups may be        replaced by O, NR⁵, S(O)_(m), C(O) or C(O)NR¹²;    -   n is independently 0, 1, 2 or 3;    -   m is independently 0.1 or 2;    -   R¹ is 3- or 4-pyridyl, 4- or 5-pyrimidinyl or 2-pyrazinyl, any        of which may be optionally substituted by one or more        substituents selected from halo, C₁₋₄ alkyl, C₁₋₄ fluoroalkyl,        C₂₋₄ alkenyl, C₂₋₄-alkynyl, C₃₋₇ cycloalkyl, aryl, OR⁶, CN, NO₂,        S(O)_(m)R⁶, CON(R⁶)₂, N(R⁶)₂, NR¹⁰COR⁶, NR¹⁰SO₂R⁶, SO₂N(R⁶)₂, a        4- to 7-membered heterocyclyl group or a 5- or 6-membered        heteroaryl group;    -   R² is 4- to 7-membered cycloalkyl substituted by R³, C(O)OR³,        C(O)R³ or S(O)₂R³, or 4- to 7-membered heterocyclyl, containing        one or two nitrogen atoms which is unsubstituted or substituted        by C(O)OR⁴, C(O)R³, S(O)₂R³, C(O)NHR⁴, P(O)(OR¹¹)₂ or a 5- or        6-membered nitrogen containing heteroaryl group;    -   R³ is C₃₋₈ alkyl, C₃₋₈ alkenyl or C₃₋₈ alkynyl, any of which may        be optionally substituted with up to 5 fluoro or chloro atoms,        and may contain a CH₂ group that may be replaced by O, or C₃₋₇        cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkylC₃₋₇        cycloalkyl, C₁₋₄ alkylaryl, C₁₋₄ alkylheterocyclyl or C₁₋₄        alkylheteroaryl, any of which may be optionally substituted with        one or more substituents selected from halo, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, OR⁶, CN, CO₂C₁₋₄ alkyl, N(R⁶)₂ and NO₂;    -   R⁴ is C₂₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl, any of which may        be optionally substituted with up to 5 fluoro or chloro atoms,        and may contain a CH₂ group that may be replaced by O, or C₃₋₇        cycloalkyl, aryl, heterocyclyl, heteroaryl, C₁₋₄ alkylC₃₋₇        cycloalkyl, C₁₋₄ alkylaryl, C₁₋₄ alkylheterocyclyl or C₁₋₄        alkylheteroaryl, any of which may be substituted with one or        more substituents selected from halo, C₁₋₄ alkyl, C₁₋₄        fluoroalkyl, OR⁶, CN, CO₂C₁₋₄ alkyl, N(R⁶)₂ and NO₂;    -   R⁵ is hydrogen, C(O)R⁷, S(O)₂R⁸, C₃₋₇ cycloalkyl or C₁₋₄ alkyl        optionally substituted by OR⁶, C₃₋₇ cycloalkyl, aryl,        heterocyclyl or heteroaryl, wherein the cyclic groups may be        substituted with one or more substituents selected from halo,        C₁₋₂ alkyl, C₁₋₂ fluoroalkyl, OR⁶, CN, N(R⁶)₂ and NO₂;    -   R⁶ are independently hydrogen, C₁₋₄ alkyl, C₃₋₇ cycloalkyl,        aryl, heterocyclyl or heteroaryl, wherein the cyclic groups may        be substituted with one or more substituents selected from halo,        C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, OR⁹, CN, SO₂CH₃, N(R¹⁰)₂ and NO₂;        or a group N(R¹⁰)₂ may form a 4- to 7-membered heterocyclic ring        optionally containing a further heteroatom selected from O and        NR¹⁰;    -   R⁷ is hydrogen, C₁₋₄ alkyl, OR⁶, N(R⁶)₂, aryl or heteroaryl;    -   R⁸ is C₁₋₄ alkyl, C₁₋₄ fluoroalkyl, aryl or heteroaryl;    -   R⁹ is hydrogen, C₁₋₂ alkyl or C₁₋₂ fluoroalkyl;    -   R¹⁰ is hydrogen or C₁₋₄ alkyl;    -   R¹¹ is phenyl; and    -   R¹² is hydrogen, C₁₋₄ alkyl or C₃₋₇ cycloalkyl.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/GB2005/050266 include the following compoundsaccording to Formula (X) (referred to herein as Group J1):4-{[Methyl-(2-pyridin-4-ylpyrimidin-4-yl)-amino]methyl}piperidine-1-carboxylicacid tert-butyl ester;4-([Methyl-(2-pyridin-4-ylpyrimidin-4-ylmethyl)amino]methyl)piperidine-1-carboxylicacid tert-butyl ester;4-[([2,4′]Bipyridinyl-6-ylmethylmethylamino)methyl]piperidine-1-carboxylicacid tert-butyl ester.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/JP02/09350 (published as WO 03/026661), the disclosure of whichis herein incorporated by reference in its entirety. Disclosed GPR119agonist in International Application No. PCT/JP02/09350 is a compound ofFormula (XI):

wherein:

-   -   —R¹¹ is a group represented by formula -A¹¹-D¹¹; wherein A¹¹ is        a single bond, lower alkylene, or lower alkenylene; and wherein        D¹¹ is an aryl, cycloalkyl, aromatic heterocycle, or a        non-aromatic heterocycle, each of which may be substituted;    -   R¹² is —H or a lower alkyl, which may be substituted by one or        more groups selected from the group consisting of aryl, halogen,        —O-lower alkyl, and —OH;    -   R¹³ is —H, methyl, or fluoro;    -   R¹⁴ is —H or a lower alkyl, which may be substituted by one or        more halogens; and    -   —R¹⁵ is a group represented by formula -A¹⁵-D¹⁵; wherein A¹⁵ is        a single bond, lower alkylene, or lower alkenylene, each of        which may be substituted; and wherein D¹⁵ is —H; —O— lower        alkyl; an amino, which may be substituted by one or two groups        selected from the group consisting of lower alkyl and aryl; or        an aryl, cycloalkyl, aromatic heterocycle, or non-aromatic        heterocycle, each of which may be substituted.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/JP02/09350 (published as WO 03/026661), the disclosure of whichis herein incorporated by reference in its entirety. Disclosed GPR119agonist in International Application No. PCT/JP02/09350 is a compound ofFormula (XII):

wherein:

-   -   R²¹ is an aryl or aromatic heterocycle, each of which may be        substituted;    -   R²² is methyl or ethyl;    -   R²³ is —H or fluoro;    -   R²⁴ is —H; and    -   R²⁵ is a lower alkyl or cycloalkyl, each of which may be        substituted.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/JP02/09350 are the following compounds according toFormula (XII) (referred to herein as Group L1):3-(2-{[2-(4-bromophenyl)-6-methylpyrimidine-4-yl]amino}ethyl)pyrrolidine1-oxide;2-{[2-(3-chloro-4-fluorophenyl)-6-ethylpyrimidine-4-yl]amino}ethanol;3-(2-{[6-methyl-2-(3,4,5-trifluorophenyl)pyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[2-(4-bromophenyl)-5-fluoro-6-methylpyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[2-(2,1,3-benzoxadiazol-5-yl)-6-methylpyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[6-ethyl-2-(3,4,5-trifluorophenyl)pyrimidine-4-yl]amino}ethyl)pyridine1-oxide;2-{[6-ethyl-2-(3,4,5-trifluorophenyl)pyrimidine-4-yl]amino}ethanol;3-2-{[2-(2,5-difluorophenyl)-6-methylpyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[2-(2,1,3-benzoxadiazol-5-yl)-6-ethylpyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[2-(4-chloro-2-fluorophenyl)-6-methylpyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[2-(4-chloro-3-fluorophenyl)-6-methylpyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[2-(5-bromo-2-fluorophenyl)-6-methylpyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[6-ethyl-2-(2,3,5-trifluorophenyl)pyrimidine-4-yl]amino}ethyl)pyridine1-oxide;3-(2-{[6-methyl-2-(2,3,5-trifluorophenyl)pyrimidine-4-yl]amino}ethyl)pyridine1-oxide.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/JP2005/018412 (published as WO 2006/040966), the disclosure ofwhich is herein incorporated by reference in its entirety. DisclosedGPR119 agonist in International Application No. PCT/JP2005/018412 is acompound of Formula (XIII):

wherein:

-   -   A is a ring selected from the group consisting of group X¹ and        group X², wherein the carbon atoms comprised by this ring can be        substituted by one or more groups selected from the group        consisting of, lower alkyl, —O-lower alkyl, halogen, carboxyl,        —CO₂-lower alkyl and carbamoyl;    -   group X¹ comprises

-   -   group X² comprises

-   -   -   —R¹ is phenyl substituted by a least one halogen; wherein            this phenyl may have further substituents; and wherein when            A is a ring selected from group X², —R¹ represents a phenyl            substituted by at least three halogens;        -   —R² is a group represented by Formula (XIIIA)

-   -   or an optionally substituted cyclic amino; wherein —R²¹ and —R²²        are the same or different and represent —H, lower alkyl, lower        alkenyl, lower alkynyl, cycloalkyl, phenyl, aromatic        heterocycle, non-aromatic heterocycle or —O-lower alkyl, wherein        each of these groups is optionally substituted; and wherein if A        is a ring selected from the group X¹, —R² represents an        optionally substituted cyclic amino.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/JP2005/018412 are the following compounds accordingto Formula (XIII) (referred to herein as Group M1):4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine;2-(4-chloro-5-fluoro-2-piperidine-1-ylphenyl)-7-methyl-4-piperidine-1-ylthieno[3,2-d]pyrimidine;[2-(4-azepane-1-ylthieno[3,2-d]pyrimidine-2-yl)-5-chloro-4-fluorophenyl]dimethylamine;2-{5-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-2-yl}ethanol;2-{5-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine-1-yl}ethanol;{1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-3-yl}aceticacid;{1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-ylidene}aceticacid;2-(4-chloro-2,5-difluorophenyl)-4-piperazine-1-ylthieno[3,2-d]pyrimidine;1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-one;2-{4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-1-yl}-2-oxoethanol;ethyl{4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-1-yl)}(oxo)acetate;4-(4-acetyl-3-methylpiperazine-1-yl)-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine;2-{1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}acetamide;1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-ol;1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-carbonitrile;(S)-3-{4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-1-yl}propane-1,2-diol;1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-oneoxime;1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4-carboxylate;ethyl({-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}oxy)acetate;(4RS,5SR)-1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]azepane-4,5-diol;{4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-2-yl}methanol;7-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]tetrahydroimidazo[1,5-a]piperazine-1,3(2H,5H)-dione;2-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]tetrahydropyrrolo[1,2-a]piperazine-6,8(2H,7H)-dione;4-azepane-1-yl-2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-6-carboxylate;{1-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperidine-4-yl}acetonitrile;2-(4-chloro-2,5-difluorophenyl)-4-[4-(1H-tetrazol-5-ylmethyl)piperidine-1-yl]thieno[3,2-d]pyrimidine;4-azepane-1-yl-2-(4-chloro-5-fluoro-2-methoxyphenyl)thieno[3,2-d]pyrimidine.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/JP2005/019000 (published as WO 2006/043490), the disclosure ofwhich is herein incorporated by reference in its entirety. DisclosedGPR119 agonist in International Application No. PCT/JP2005/019000 is acompound of Formula (XIV):

wherein:

-   -   A is a ring selected from the group consisting of group X¹,        group X², group X³ and group X⁴, wherein the carbon atoms        comprised by this ring may be substituted by one or more groups,        selected from the group consisting of, lower alkyl, —O-lower        alkyl, halogen, carboxyl, —CO₂-lower alkyl and carbamoyl, and        wherein the sulfur atoms comprised by this ring may be oxidized;    -   group X¹ is a group comprising

-   -   group X² is a group comprising

-   -   group X³ is a group comprising

-   -   group X⁴ is a group comprising

-   -   —R¹ is a group selected from (1) to (3) below:        -   (1) Phenyl substituted by at least one halogen, wherein this            phenyl may have further substituents;        -   (2) Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or            cycloheptyl, each of which may be substituted;        -   (2) Pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl,            thienyl, thiazolyl, oxazolyl, imidazolyl, isothiazolyl,            isooxazolyl, pyrazolyl, or furyl substituted by at least one            halogen; wherein these rings may be substituted by one or            more halogens, which are the same or different; and wherein            these rings are bonded via a carbon atom comprised by these            rings to position 2 of the pyrimidine ring in the Formula            (XIV);    -   wherein when A is a ring selected from group X⁴, —R¹ represents        a phenyl that is substituted by at least three halogens;        -   —R² is the group represented by a Formula (XIVA)

-   -   or an optionally substituted cyclic amino;        -   wherein —R²¹ and —R²² are the same or different and            represent —H, lower alkyl, lower alkenyl, lower alkynyl,            cycloalkyl, phenyl, aromatic heterocycle, non-aromatic            heterocycle or —O-lower alkyl, wherein each of these groups            may be substituted;    -   wherein when A is a ring selected from group X² or group X³, —R²        represents an optionally substituted cyclic amino.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of GPR119 agonists disclosed in InternationalApplication No. PCT/JP2005/019000 are the following compounds accordingto Formula (XIV) (referred to herein as Group N1):(R)-2-(4-chloro-2,5-difluorophenyl)-4-(3-methylpiperidin-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidine-6,6-dioxide;4-{1-[2-(4-chloro-2,5-difluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]piperidin-4-yl}butanicacid;{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxo-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-ylidine}aceticacid;2-(4-chloro-2,5-difluorophenyl)-4-piperazin-1-yl-5,7-dihydrothieno[3,4-d]pyrimidine;2-{4-[2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperazin-1-yl}-2-oxoethanol;2-(4-chloro-2,5-difluorophenyl)-4-[4-(methylsulfonyl)piperazin-1-yl]-5,7-dihydrothieno[3,4-d]pyrimidine;[1-(2-cyclopentyl-6,6-dioxo-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl)piperidin-4-yl]acetamide;1-{2-[2,5-difluoro-4-(methylthio)phenyl]-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl}-1,4-diazepane-5-one;4-[6,6-dioxide-4-(5-oxo-1,4-diazepan-1-yl)-5,7-dihydrothieno[3,4-d]pyrimidin-2-yl]-2,5-difluorobenzonitrile;3-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}propane-1-ol;2-({1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}amino)ethanol;2-{8-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]deca-2-yl)}ethanol;(2Z)-3-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}prop-2-en-1-ol;(4R,5S)-1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]azepane-4,5-diol;N-(2-aminoethyl)-N-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-β-alanine;{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}acetonitrile;1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl(2-hydroxyethyl)methylcarbamate;1-{-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}pyrrolidin-2-one;3-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl}-1,3-oxazolidin-2-one;4-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-N-ethylpiperazine-1-carboxamide;2-(4-chloro-2,5-difluorophenyl)-N-cyclohexane-3-en-1-yl-5,7-dihydrothieno[3,4-d]pyrimidine-4-amine6,6-dioxide;3-{1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxide-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]-4-hydroxypiperidin-4-yl}propylacetate.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2006/050176 (published as WO 2007/003960), the disclosure ofwhich is herein incorporated by reference in its entirety.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2006/050177 (published as WO 2007/003961), the disclosure ofwhich is herein incorporated by reference in its entirety:

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2006/050178 (published as WO 2007/003962), the disclosure ofwhich is herein incorporated by reference in its entirety.

Examples of GPR119 agonists are described in International ApplicationNo. PCT/GB2006/050182 (published as WO 2007/003964), the disclosure ofwhich is herein incorporated by reference in its entirety.

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (I).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (II).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (III).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (IV).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (V).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (VI).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (VI), provided that the compound is not identical to4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine,4-(3-pyridin-4-yl-[1,2,4]oxadiazol-5-yl)piperidine-1-carboxylic acidbutyl ester, 4-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine,3-[5-(4-butylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine, or3-[5-(4-propylcyclohexyl)-[1,2,4]oxadiazol-3-yl]pyridine,

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (VII).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (VIII).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (IX).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (X).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (XI).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (XII).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (XII), provided that when in Formula (XII) R²² is methyl andR²³ is —H, R²⁵ in Formula (XII) is not: an unsubstituted lower alkyl;ethyl or propyl, each of which is substituted by a dimethylamino or adiisopropylamino; methyl substituted by a carbamoyl, which issubstituted by two identical or different groups selected from the groupconsisting of lower alkyl and phenyl; or methyl substituted by phenyl,which may be substituted.

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (XII), provided that the compound is not identical to6-methyl-N-(2-morpholine-4-ylethyl)-2-phenylpyrimidine-4-amine,6-methyl-2-(4-methoxyphenyl)-N-(2-morpholine-4-ylethyl)pyrimidine-4-amine,2-{[6-methyl-2-(6-methylpyridine-2-yl)pyrimidine-4-yl]amino}ethanol,2-{[2-(4-bromophenyl)-6-methylpyrimidine-4-yl]amino}ethanol, or[2-(4-bromophenyl)-6-methylpyrimidine-4-yl](cyclohexyl)amino.

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (XIII).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (XIV).

In one aspect of the present invention, the GPR119 agonist is a compoundof Formula (XIV), provided that the compound is not identical to2-(2-fluorophenyl)-N,N-dimethyl-5,7-dihydrothieno[3,4-d]pyrimidine-4-amineor 2-cyclopropyl-4-piperazin-1-yl-5,7-dihydrothieno[3,4-d]pyrimidine.

In one aspect of the present invention, the GPR119 agonist is a compoundselected from Group A1, Group B1, Group B2, Group B3, Group B4, GroupB5, Group C1, Group C2, Group C3, Group C4, Group C5, Group C6, GroupC7, Group C8, Group C9, Group C10, Group D1, Group D2, Group D3, GroupD4, Group D5, Group D6, Group D7, Group D8, Group D9, Group D10, GroupD11, Group D12, Group D13, Group D14, Group E1, Group E2, Group F1,Group G1, Group G2, Group G3, Group H1, Group I1, Group J1, Group L1,Group M1, or Group N1.

In one aspect, the GPR119 agonist is selected from the left column ofTable D. It is expressly contemplated that each individual GPR119agonist from the left column of Table D is a separate embodiment withinthe scope of the present invention.

In one aspect, the GPR119 agonist is selected from any set of compoundsselected from the left column of Table D.

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/US2004/001267 (published as WO04/065380).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/US2004/005555 (published as WO04/076413).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/US2004/022327 (published as WO05/007647).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/US2004/022417 (published as WO05/007658).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/US2005/019318 (published as WO2005/121121).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2004/050046 (published as WO2005/061489).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/US06/00567 (published as WO2006/083491).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2005/050264 (published as WO2006/067531).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2005/050265 (published as WO2006/067532).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2005/050266 (published as WO2006/070208).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/JP02/09350 (published as WO03/026661).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/JP2005/018412 (published as WO06/040966).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/JP2005/019000 (published as WO2006/043490).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2006/050176 (published as WO2007/003960).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2006/050177 (published as WO2007/003961).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2006/050178 (published as WO2007/003962).

In one aspect, the GPR119 agonist is identical to a compound disclosedin International Application No. PCT/GB2006/050182 (published as WO2007/003964).

Other examples of GPR119 agonists may be found in InternationalApplication No. PCT/JP02/09350 (published as WO 03/026661), thedisclosure of which is herein incorporated by reference in its entirety.GPR119 agonists disclosed in International Application No.PCT/JP02/09350 include but are not limited to the compounds in Table A.

TABLE A Cmpd No. Chemical Structure Chemical Name  1A

[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-methyl-amine  2A

[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-p-tolyl-amine  3A

[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-(4-methoxy- phenyl)-amine 4A

[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-phenyl-amine  5A

[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-cyclohexyl-amine  6A

5-[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-ylamino]-pentan-1-ol  7A

3-[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-ylamino]- propionitrile  8A

[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-yl]-(4-fluoro-benzyl)- amine 9A

[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-yl]-[2-(4-chloro-phenyl)-ethyl]-amine 10A

[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-yl]-pyridin-2- ylmethyl-amine11A

[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-pyridin-3- ylmethyl-amine12A

3-{[2-(4-Bromo-phenyl)-6- methyl-pyrimidin-4-ylamino]-methyl}-1H-pyridin-2-one 13A

4-{[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-ylamino]-methyl }-1H-pyridin-2-one 14A

4-{2-[2-(4-Bromo-phenyl)-6- methyl-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one 15A

[2-(3-Chloro-4-fluoro-phenyl)-6- ethyl-pyrimidin-4-yl]-(1,1-dioxo-hexahydro-116-thiopyran-4-yl)- amine 16A

[6-Methyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine 17A

[6-Ethyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine 18A

[6-Methyl-2-(2,4,5-trifluoro- phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3-yl)-ethyl]-amine 19A

4-{4-Methyl-6-[2-(1-oxy-pyridin- 3-yl)-ethylamino]-pyrimidin-2-yl}-benzonitrile 20A

2-[4-(6-Methyl-2-phenyl- pyrimidin-4-ylamino)-phenyl]- ethanol 21A

[2-(3-Chloro-phenyl)-6-methyl- pyrimidin-4-yl]-methyl-amine 22A

2-{[2-(4-Bromo-phenyl)-6- methyl-pyrimidin-4-yl]-methyl- amino}-ethanol;compound with methane

Examples of GPR119 agonists may be found in International Application JP2004269468, the disclosure of which is herein incorporated by referencein its entirety. GPR119 agonists disclosed in JP 2004269468 include butare not limited to the compounds in Table B.

TABLE B Cmpd No. Chemical Structure Chemical Name 1B

3-[6-Ethyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol 2B

(S)-3-[6-Methyl-2-(2,3,5-trifluoro- phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol 3B

[2-(4-Bromo-3-fluoro- phenyl)-6-methyl-pyrimidin-4-ylamino]-propane-1,2-diol 4B

(R)-3-[6-Ethyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol 5B

(R)-3-[2-(3-Chloro-4-fluoro- phenyl)-6-ethyl-pyrimidin-4-ylamino]-propane-1,2-diol 6B

(R)-3-[2-(4-Bromo-2,5-difluoro- phenyl)-5-fluoro-6-methyl-pyrimidin-4-ylamino]-propane- 1,2-diol 7B

(R)-3-[2-(4-Chloro-2,5-difluoro- phenyl)-6-difluoromethyl-pyrimidin-4-ylamino]-propane- 1,2-diol

Examples of GPR119 agonists may be found in International Application JP2004269469, the disclosure of which is herein incorporated by referencein its entirety. GPR119 agonists disclosed in JP 2004269469 include butare not limited to the compounds in Table C.

TABLE C Cmpd No. Chemical Structure Chemical Name 1C

5-{2-[2-(4-Bromo-phenyl)-6- ethyl-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one 2C

5-{2-[6-Methyl-2-(2,4,5-trifluoro- phenyl)-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one 3C

4-{2-[2-(4-Chloro-2,5-difluoro- phenyl)-6-ethyl-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one 4C

6-Chloro-4-{2-[6-methyl-2-(2,4,5- trifluoro-phenyl)-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one 5C

4-{1-Hydroxy-2-[6-methyl-2- (2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-ethyl}-1H- pyridin-2-one 6C

4-{1-Methyl-2-[6-methyl-2- (2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-ethyl}-1H- pyridin-2-one

In one aspect, the GPR119 agonist is identical to a compound disclosedin WO 03/026661.

In one aspect, the GPR119 agonist is a compound selected from Table A.

In one aspect, the GPR119 agonist is identical to a compound disclosedin JP 2004269468.

In one aspect, the GPR119 agonist is a compound selected from Table B.

In one aspect, the GPR119 agonist is identical to a compound disclosedin JP 2004269469.

In one aspect, the GPR119 agonist is a compound selected from Table C.

In one aspect of the present invention, the GPR119 agonist has an EC₅₀of less than about 10 μM, less than about 1 μM, less than about 100 nM,less than about 75 nM, less than about 50 nM, less than about 25 nM,less than about 20 nM, less than about 15 nM, less than about 10 nM,less than about 5 nM, less than about 4 nM, less than about 3 nM, lessthan about 2 nM, or less than about 1 nM. In certain embodiments, theGPR119 agonist has an EC₅₀ of less than about 50 nM, less than about 25nM, less than about 20 nM, less than about 15 nM, less than about 10 nM,less than about 5 nM, less than about 4 nM, less than about 3 nM, lessthan about 2 nM, or less than about 1 nM.

In one aspect of the present invention, the GPR119 agonist is aselective GPR119 agonist, wherein the selective GPR119 agonist has aselectivity for GPR119 over corticotrophin-releasing factor-1 (CRF-1)receptor of at least about 10-fold, of at least about 100-fold, or of atleast about 1000-fold. In one aspect of the present invention, theGPR119 agonist is a selective GPR119 agonist, wherein the selectiveGPR119 agonist has a selectivity for GPR119 overcorticotrophin-releasing factor-1 (CRF-1) receptor of at least about100-fold.

In one aspect of the present invention, the GPR119 agonist is a smallmolecule.

In one aspect of the present invention, the GPR119 agonist is orallyactive.

It is expressly contemplated that a GPR119 agonist of the invention isan agonist of an endogenous GPR119.

In one aspect of the present invention, the GPR119 agonist is an agonistof human GPR119 (e.g., human GPR119, GenBank® Accession No. AAP72125 andalleles thereof).

In one aspect of the present invention, any one or more GPR119 agonistcan be excluded from any embodiment of the present invention.

DPP-IV Inhibitors

The class of DPP-IV inhibitors useful in the novel therapeuticcombinations of the present invention include compounds which exhibit anacceptably high affinity for DPP-IV. The DPP-IV inhibitor orpharmaceutically acceptable salt may be any DPP-IV inhibitor, and inparticular embodiment a selective dipeptidyl peptidase inhibitor, and infurther particular embodiment a selective DPP-IV inhibitor.

Examples of DPP-IV inhibitors are described in International ApplicationNo. PCT/US02/21349 (published as WO 03/004498), the disclosure of whichis herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US02/21349 as a DPP-IV inhibitor is acompound of Formula (XIX):

wherein:

-   -   Ar is phenyl which is unsubstituted or substituted with 1-5 of        R³, wherein R³ is independently selected from the group        consisting of:        -   (1) halogen,        -   (2) C₁₋₆alkyl, which is linear or branched and is            unsubstituted or substituted with 1-5 halogens,        -   (3) OC₁₋₆alkyl, which is linear or branched and is            unsubstituted or substituted with 1-5 halogens, and        -   (4) CN;    -   X is selected from the group consisting of:        -   (1) N, and        -   (2) CR²;    -   R¹ and R² are independently selected from the group consisting        of:        -   (1) hydrogen,        -   (2) CN,        -   (3) C₁₋₁₀alkyl, which is linear or branched and which is            unsubstituted or substituted with 1-5 halogens or phenyl,            which is unsubstituted or substituted with 1-5 substituents            independently selected from halogen, CN, OH, R⁴, OR⁴,            NHSO₂R⁴, SO₂R⁴, CO₂H, and CO₂C₁₋₆alkyl, wherein the            CO₂C₁₋₆alkyl is linear or branched,        -   (4) phenyl which is unsubstituted or substituted with 1-5            substituents independently selected from halogen, CN, OH,            R⁴, OR⁴, NHSO₂R⁴, SO₂R⁴, CO₂H, and CO₂C₁₋₆alkyl, wherein the            CO₂C₁₋₆alkyl is linear or branched, and        -   (5) a 5- or 6-membered heterocycle which may be saturated or            unsaturated comprising 1-4 heteroatoms independently            selected from N, S and O, the heterocycle being            unsubstituted or substituted with 1-3 substituents            independently selected from oxo, OH, halogen, C₁₋₆alkyl, and            OC₁₋₆alkyl, wherein the C₁₋₆alkyl and OC₁₋₆alkyl are linear            or branched and optionally substituted with 1-5 halogens;    -   R⁴ is C₁₋₆alkyl, which is linear or branched and which is        unsubstituted or substituted with 1-5 groups independently        selected from halogen, CO₂H, and CO₂C₁₋₆alkyl, wherein the        CO₂C₁₋₆alkyl is linear or branched.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of DPP-IV inhibitors disclosed in InternationalApplication No. PCT/US02/21349 include the following compounds accordingto Formula (XIX) (referred to herein, as Group S1):7-[(3R)-3-Amino-4-(3,4-difluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine;7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine;7-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine;7-[3(R)-3-Amino-4-(3,4-difluorophenyl(butanoyl]-5,6,7,8-tetrahydroimidazo[1,2-α]pyrazine;7-[(3R)-3-Amino-4-(3,4-difluorophenyl)butanoyl]-3-ethyl-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine;7-[(3R)-3-Amino-4-(2,5-difluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro1,2,4-triazolo[4,3-α]pyrazine;7-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-α]pyrazine.

Examples of DPP-IV inhibitors are described in International ApplicationNo. PCT/EP99/09708 (published as WO 00/34241), the disclosure of whichis herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/EP99/09708 as a DPP-IV inhibitor is acompound of Formula (XX):

wherein:

-   -   R is substituted adamantyl; and    -   n is 0 to 3.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of DPP-IV inhibitors disclosed in InternationalApplication No. PCT/EP99/09708 include the following compounds accordingto Formula (XX) (referred to herein as Group T1): pyrrolidine,1-[[(3,5-dimethyl-1-adamantyl)amino]-acetyl]-2-cyano-, (S)—;pyrrolidine, 1-[[(3-ethyl-1-adamantyl)amino]acetyl]-2-cyano-, (S)—;pyrrolidine, 1-[[(3-methoxy-1-adamantyl)amino]-acetyl]-2-cyano-, (S)—;pyrrolidine,1-[[[3-[[(t-butylamino)carbonyl]oxy]-1-adamantyl]amino]acetyl]-2-cyano-,(S)—; pyrrolidine,1-[[[3-[[[(4-methoxyphenyl)amino]carbonyl]oxy]-1-adamantyl]amino]acetyl]-2-cyano-,(S)—; pyrrolidine,1-[[[3-[[(phenylamino)carbonyl]oxy]-1-adamantyl]amino]acetyl]-2-cyano-,(S)—; pyrrolidine, 1-[[(5-hydroxy-2-adamantyl)amino]-acetyl]-2-cyano-,(S)—; pyrrolidine; 1-[[(3-acetyloxy-1-adamantyl)amino]-acetyl]-2-cyano-,(S)—; pyrrolidine,1-[[[3-[[[(diisopropyl)amino]carbonyl]oxy]-1-adamantyl]amino]acetyl]-2-cyano-,(S)—; pyrrolidine,1-[[[3-[[[(cyclohexyl)amino]carbonyl]oxy]-1-adamantyl]amino]acetyl]-2-cyano-,(S)—; pyrrolidine, 1-[[(3-ethoxy-1-adamantyl)amino]acetyl]-2-cyano-,(S)—.

Examples of DPP-IV inhibitors are described in International ApplicationNo. PCT/US01/07151 (published as WO 01/68603), the disclosure of whichis herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US01/07151 as a DPP-IV inhibitor is acompound of Formula (XXI):

wherein:

-   -   x is 0 or 1 and y is 0 or 1, provided that        -   x=1 when y=0 and        -   x=0 when y=1;    -   n is 0 or 1;    -   X is H or CN;    -   R¹, R², R³ and R⁴ are the same or different and are        independently selected from hydrogen, alkyl, alkenyl, alkynyl,        cycloalkyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl,        alkylcycloalkyl, hydroxyalkyl, hydroxyalkylcycloalkyl,        hydroxycycloalkyl, hydroxybicycloalkyl, hydroxytricycloalkyl,        bicycloalkylalkyl, alkylthioalkyl, arylalkylthioalkyl,        cycloalkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl,        cycloheteroalkyl or cycloheteroalkylalkyl; all optionally        substituted through available carbon atoms with 1, 2, 3, 4 or 5        groups selected from hydrogen, halo, alkyl, polyhaloalkyl,        alkoxy, haloalkoxy, polyhaloalkoxy, alkoxycarbonyl, alkenyl,        alkynyl, cycloalkyl, cycloalkylalkyl, polycycloalkyl,        heteroarylamino, arylamino, cycloheteroalkyl,        cycloheteroalkylalkyl, hydroxy, hydroxyalkyl, nitro, cyano,        amino, substituted amino, alkylamino, dialkylamino, thiol,        alkylthio, alkylcarbonyl, acyl, alkoxycarbonyl, aminocarbonyl,        alkenylaminocarbonyl, alkylaminocarbonyl, alkenylaminocarbonyl,        alkylcarbonyloxy, alkylcarbonylamino, arylcarbonylamino,        alkylsulfonylamino, alkylaminocarbonylamino,        alkoxycarbonylamino, alkylsulfonyl, aminosulfinyl,        aminosulfonyl, alkylsulfinyl, sulfonamido or sulfonyl;    -   and R¹ and R³ may optionally be taken together to form        —(CR⁵R⁶)_(m)— where m is 2 to 6, and R⁵ and R⁶ are the same or        different and are independently selected from hydroxy, alkoxy,        H, alkyl, alkenyl, alkynyl, cycloalkyl, halo, amino, substituted        amino, cycloalkylalkyl, cycloalkenyl, aryl, arylalkyl,        heteroaryl, heteroarylalkyl, cycloheteroalkyl,        cycloheteroalkylalkyl, alkylcarbonylamino, arylcarbonylamino,        alkoxycarbonylamino, aryloxycarbonylamino, alkoxycarbonyl,        aryloxycarbonyl, or alkylaminocarbonylamino, or R¹ and R⁴ may        optionally be taken together to form —(CR⁷R⁸)_(p)— wherein p is        2 to 6, and R⁷ and R⁸ are the same or different and are        independently selected from hydroxy, alkoxy, cyano, H, alkyl,        alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,        halo, amino, substituted amino, aryl, arylalkyl, heteroaryl,        heteroarylalkyl, cycloheteroalkyl, cycloheteroalkylalkyl,        alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino,        aryloxycarbonylamino, alkoxycarbonyl, aryloxycarbonyl, or        alkylaminocarbonylamino, or optionally R¹ and R³ together with

form a 5 to 7 membered ring containing a total of 2 to 4 heteroatomsselected from N, O, S, SO, or SO₂;

-   -   or optionally R¹ and R³ together with

form a 4 to 8 membered cycloheteroalkyl ring wherein thecycloheteroalkyl ring has an optional aryl ring fused thereto or anoptional 3 to 7 membered cycloalkyl ring fused thereto.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Examples of DPP-IV inhibitors are described in International ApplicationNo. PCT/US2004/042209 (published as WO 2005/095381), the disclosure ofwhich is herein incorporated by reference in its entirety. Disclosed inInternational Application No. PCT/US2004/042209 as a DPP-IV inhibitor isa compound of Formula (XXII):

wherein:

-   -   M₀ is —C-LX, N or CR₄;    -   Q¹ and Q² are each independently selected from the group        consisting of CO, CS, SO, SO₂, and C═NR₉;    -   R₀ is R₁ or -LX, with the proviso that only one of R₀ and M₀ is        -LX;    -   R₁ is hydrogen or is selected from the group consisting of halo,        perhalo(C₁₋₁₀)alkyl,

amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl,arylalkyl, heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl,thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl, sulfinyl C(₁₋₃)alkyl,imino(C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, carbonylgroup, imino group, sulfonyl group and sulfinyl group, each substitutedor unsubstituted;

-   -   R₂ is hydrogen or selected from the group consisting of        (C₁₋₁₀)alkyl, C(₃₋₁₂)cycloalkyl, (C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl,        hetero(C₃₋₁₂)cycloalkyl(C₁₋₅)alkyl, hetero(C₃₋₁₂)cycloalkyl,        aryl(C₁₋₁₀)alkyl, heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, hetero(C₄₋₁₂)bicycloaryl(C₁₋₅)alkyl,        carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl,        sulfonyl(C₁₋₃)alkyl, sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl,        amino, aryl, heteroaryl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl group, imino group, sulfonyl group and        sulfinyl group, each substituted or unsubstituted;    -   R₃ is selected from the group consisting of perhalo(C₁₋₁₀)alkyl,        amino, (C₁₋₁₀)alkyl, cycloalkyl, heterocycloalkyl, arylalkyl,        heteroarylalkyl, aryl, heteroaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy,        heteroaryloxy, carbonyl group, imino group, sulfonyl group and        sulfinyl group, each substituted or unsubstituted, and a        substituted or unsubstituted 3, 4, 5, 6 or 7 membered ring;

R₄ is hydrogen or is selected from the group consisting of halo,perhalo(C₁₋₁₀)alkyl, amino, cyano, thio, (C₁₋₁₀)alkyl, cycloalkyl,heterocycloalkyl, arylalkyl, heteroarylalkyl, aryl, heteroaryl,carbonyl(C₁₋₃)alkyl, thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, hydroxy, alkoxy, aryloxy,heteroaryloxy, carbonyl group, imino group, sulfonyl group and sulfinylgroup, each substituted or unsubstituted;

-   -   R₉ is hydrogen or is selected from the group consisting of        alkyl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl,        bicycloaryl, and heterobicycloaryl, each substituted or        unsubstituted;    -   L is a linker providing 1, 2 or 3 atom separation between X and        the ring to which L is attached, wherein the atoms of the linker        providing the separation are selected from the group consisting        of carbon, oxygen, nitrogen, and sulfur; and    -   X is selected from the group consisting of (C₁₋₁₀)alkyl,        (C₃₋₁₂)cycloalkyl, hetero(C₃₋₁₂)cycloalkyl, aryl(C₁₋₁₀)alkyl,        heteroaryl(C₁₋₅)alkyl, (C₉₋₁₂)bicycloaryl,        hetero(C₄₋₁₂)bicycloaryl, carbonyl(C₁₋₃)alkyl,        thiocarbonyl(C₁₋₃)alkyl, sulfonyl(C₁₋₃)alkyl,        sulfinyl(C₁₋₃)alkyl, imino(C₁₋₃)alkyl, amino, aryl, heteroaryl,        hydroxy, alkoxy, aryloxy, heteroaryloxy, alkenyl, alkynyl,        carbonyl group, cyano, imino group, sulfonyl group and sulfinyl        group, each substituted or unsubstituted.

The present invention also encompasses diastereomers as well as opticalisomers, e.g. mixtures of enantiomers including racemic mixtures, aswell as individual enantiomers and diastereomers, which arise as aconsequence of structural asymmetry in certain compounds of theinvention. Separation of the individual isomers or selective synthesisof the individual isomers is accomplished by application of variousmethods which are well known to practitioners in the art.

Specific examples of DPP-IV inhibitors disclosed in InternationalApplication No. PCT/US2004/042209 include the following compoundsaccording to Formula (XXII) (referred to herein as Group V1):2-(6-Chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile;2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione;6-[3-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione;6-[3-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;6-[3-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;6-[3-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;6-[3-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;2-{6-[Azepan-3(±)-ylamino]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3(±)-Amino-azepan-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-(2-Amino-ethylamino)-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}benzonitrile;2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;6-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile;3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoicacid methyl ester;3-{4-[3-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoicacid;6-[3-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione;2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;6-[3(R)-Amino-piperidin-1-yl]-1-(2,5-di-chloro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-3,6-di-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;(R)-2-((6-(3-amino-3-methylpiperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)methyl)-4-fluorobenzonitrile;2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile.

Specific examples of DPP-IV inhibitors disclosed in InternationalApplication No. PCT/US2004/042209 include the following compoundsaccording to Formula (XXII) (referred to herein as Group V2):2-{6-[3(R)-Amino-piperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}benzonitrile;2-{6-[3(R)-Amino-piperidin-1-yl]-3-ethyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3(R)-Amino-piperidin-1-yl]-5-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-1H-pyrimidine-2,4-dione;6-[3(R)-Amino-piperidin-1-yl]-1-(2-iodo-benzyl)-1H-pyrimidine-2,4-dione;6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;6-{[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-5-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;6-[3(R)-Amino-piperidin-1-yl]-1-(2-chloro-4-fluoro-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;6-[3(R)-Amino-piperidin-1-yl]-1-(2-bromo-benzyl)-3-methyl-1H-pyrimidine-2,4-dione;2-{6-[3(R)-Amino-piperidin-1-yl]-3-(3-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3(R)-Amino-piperidin-1-yl]-3-(4-cyano-benzyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-[6-(3-Amino-piperidin-1-yl)-3-(1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-benzonitrile;2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(4-pyrazol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;2-{6-[3(R)-Amino-piperidin-1-yl]-2,4-dioxo-3-(3-pyrrol-1-yl-benzyl)-3,4-dihydro-2H-pyrimidin-1-ylmethyl}-benzonitrile;6-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl]-thiophene-3-carbonitrile;3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoicacid methyl ester;3-{4-[3(R)-Amino-piperidin-1-yl]-3-(2-cyano-benzyl)-2,6-dioxo-3,6-dihydro-2H-pyrimidin-1-ylmethyl}-benzoicacid;6-[3(R)-Amino-piperidin-1-yl]-1,3-bis-(2-bromo-5-fluoro-benzyl)-1H-pyrimidine-2,4-dione;2-[6-(3(R)-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile.

Examples of DPP-IV inhibitors are described in Villhauer et al., J MedChem (2003) 46:2774-2789, for LAF237; Ahren et al, J Clin EndocrinolMetab (2004) 89:2078-2084; Villhauer et al., J Med Chem (2002)45:2362-2365 for NVP-DPP728; Ahren et al, Diabetes Care (2002)25:869-875 for NVP-DPP728; Peters et al., Bioorg Med Chem Lett (2004)14:1491-1493; Caldwell et al., Bioorg Med Chem Lett (2004) 14:1265-1268;Edmondson et al., Bioorg Med Chem Lett (2004) 14:5151-5155; and Abe etal., J Nat Prod (2004) 67:999-1004; the disclosure of each of which isherein incorporated by reference in its entirety.

Specific examples of DPP-IV inhibitors include, but are not limited to,dipeptide derivatives or dipeptide mimetics such as alanine-pyrrolidide,isoleucine-thiazolidide, and the pseudosubstrate N-valyl prolyl,O-benzoyl hydroxylamine, as described e.g. in U.S. Pat. No. 6,303,661,the disclosure of which is herein incorporated by reference in itsentirety.

Examples of DPP-IV inhibitors may be found in U.S. Pat. Nos. 7,074,794,7,060,722, 7,053,055, 7,026,316, 7,022,718, 6,949,515, 6,897,222,6,869,947, 6,867,205, 6,861,440, 6,849,622, 6,812,350, 6,803,357,6,800,650, 6,727,261, 6,716,843, 6,710,040, 6,706,742, 6,645,995,6,617,340, 6,699,871, 6,573,287, 6,432,969, 6,395,767, 6,380,398,6,303,661, 6,242,422, 6,166,063, 6,100,234, 6,040,145, the disclosure ofeach of which is herein incorporated by reference in its entirety.Examples of DPP-IV inhibitors may be found in U.S. Pat. Appl. Nos.2006142576, 2006135767, 2006135512, 2006111336, 2006074087, 2006069116,2006052382, 2006046978, 2006040963, 2006039974, 2006024313, 2006014764,2005059724, 2005059716, 2005043292, 2005038020, 2005032804, 2005004205,2004259903, 2004259902, 2004259883, 2004254226, 2004242898, 2004229926,2004180925, 2004176406, 2004138214, 2004116328, 2004110817, 2004106656,2004097510, 2004087587, 2004082570, 2004077645, 2004072892, 2004063935,2004034014, 2003232788, 2003225102, 2003216450, 2003216382, 2003199528,2003195188, 2003162820, 2003149071, 2003134802, 2003130281, 2003130199,2003125304, 2003119750, 2003119738, 2003105077, 2003100563, 2003087950,2003078247, 2002198205, 2002183367, 2002103384, 2002049164, 2002006899,the disclosure of each of which is herein incorporated by reference in,its entirety.

Examples of DPP-IV inhibitors may be found in International ApplicationsWO 2006/071762, wo 2006/071752, WO 2006/068978, WO 2006/068163, WO2006/058628, WO 2006/058064, WO 2006/040625, WO 2006/039325, WO2006/033848, WO 2006/030847, WO 2006/027204, WO 2006/023750, WO2006/020017, WO 2006/015699, WO 2006/015691, WO 2006/013104, WO2006/012441, WO 2006/012395, WO 2006/011035, WO 2006/009886, WO2005/123685, WO 2005/121131, WO 2005/121089, WO 2005/120494, WO2005/118555, WO 2005/116029, WO 2005/116014, WO 2005/115982, WO2005/108382, WO 2005/106011, WO 2005/100334, WO 2005/095339, WO2005/094323, WO 2005/087235, WO 2005/082849, WO 2005/082348, WO2005/079795, WO 2005/075426, WO 2005/072530, WO 2005/063750, WO2005/058849, WO 2005/049022, WO 2005/047297, WO 2005/044195, WO2005/042533, WO 2005/042488, WO 2005/040095, WO 2005/037828, WO2005/037779, WO 2005/034940, WO 2005/033099, WO 2005/032590, WO2005/030751. WO 2005/030127, WO 2005/026148, WO 2005/025554, WO2005/023762, WO 2005/020920, WO 05/19168, WO 05/12312, WO 05/12308, WO05/12249, WO 05/11581, WO 05/09956, WO 05/03135, WO 05/00848, WO05/00846, WO 04/112701, WO 04/111051, WO 04/111041, WO 04/110436, WO04/110375, WO 04/108730, WO 04/104216, WO 04/104215, WO 04/103993, WO04/103276, WO 04/99134, WO 04/96806, WO 04/92128, WO 04/87650, WO04/87053, WO 04/85661, WO 04/85378, WO 04/76434, WO 04/76433, WO04/71454, WO 04/69162, WO 04/67509, WO 04/64778, WO 04/58266, WO04/52362, WO 04/52850, WO 04/50022, WO 04/50658, WO 04/48379, WO04/46106, WO 04/43940, WO 04/41820, WO 04/41795, WO 04/37169, WO04/37181, WO 04/33455, WO 04/32836, WO 04/20407, WO 04/18469, WO04/18468, WO 04/18467, WO 04/14860, WO 04/09544, WO 04/07468, WO04/07446, WO 04/04661, WO 04/00327, WO 03/106456, WO 03/104229, WO03/101958, WO 03/101448, WO 03/99279, WO 03/95425, WO 03/84940, WO03/82817, WO 03/80633, WO 03/74500, WO 03/72556, WO 03/72528, WO03/68757, WO 03/68748, WO 03/57666, WO 03/57144, WO 03/55881, WO03/45228, WO 03/40174, WO 03/38123, WO 03/37327, WO 03/35067, WO03/35057, WO 03/24965, WO 03/24942, WO 03/22871, WO 03/15775, WO03/04498, WO 03/04496, WO 03/02530, WO 03/02596, WO 03/02595, WO03/02593, WO 03/02553, WO 03/02531, WO 03/00181, WO 03/00180, WO03/00250, WO 02/83109, WO 02/83128, WO 02/76450, WO 02/68420, WO02/62764, WO 02/55088, WO 02/51836, WO 02/38541, WO 02/34900, WO02/30891, WO 02/30890, WO 02/14271, WO 02/02560, WO 01/97808, WO01/96295, WO 01/81337, WO 01/81304, WO 01/68603, WO 01/55105, WO01/52825, WO 01/34594, WO 00/71135, WO 00/69868, WO 00/56297, WO00/56296, WO 00/34241, WO 00/23421, WO 00/10549, WO 99/67278, WO99/62914, WO 0.99/61431, WO 99/56753, WO 99/25719, WO 99/16864, WO98/50066, WO 98/50046, WO 98/19998, WO 98/18763, WO 97/40832, WO95/29691, WO 95/15309, WO 93/10127, WO 93/08259, WO 91/16339, EP1671649, EP 1667524, EP 1664031, EP 1659123, EP 1658066, EP 1638970, EP1638968, EP 1638950, EP 1635818, EP 1627870, EP 1625122, EP 1624874, EP1517907, EP 1513808, EP 1492777, EP 1490335, EP 1489088, EP 1480961, EP1476435, EP 1476429, EP 1469873, EP 1465891, EP 1463727, EP 1461337, EP1450794, EP 1446116, EP 1442049, EP 1441719, EP 1426366, EP 1412357,EP1406873, EP 1406872, EP 1406622, EP 1404675, EP 1399420, EP 1399471,EP 1399470, EP 1399469, EP 1399433, EP 1399154, EP 1385508, EP 1377288,EP 1355886, EP 1354882, EP 1338592, EP 1333025, EP 1323710, EP 1304327,EP 1301187, EP 1296974, EP 1280797, EP 1282600, EP 1261586, EP 1258476,EP 1254113, EP 1248604, EP 1245568, EP 1215207, EP 1228061, EP 1137635,EP 1123272, EP 1104293, EP 1082314, EP 1050540, EP 1043328, EP 0995440,EP 0980249, EP 0975359, EP 0731789, EP 0641347, EP 0610317, EP 0528858,CA 2466870, CA 2433090, CA 2339537, CA 2289125. CA 2289124, CA 2123128,DD 296075, DE 19834591, DE 19828113, DE 19823831, DE 19616486, DE10333935, DE 10327439, DE 10256264, DE 10251927, DE 10238477, DE10238470, DE 10238243, DE 10143840, FR 2824825, FR 2822826,JP2005507261, JP 2005505531, JP 2005502624, JP 2005500321, JP2005500308, JP2005023038, JP 2004536115, JP 2004535445, JP 2004535433,JP 2004534836, JP 2004534815, JP 2004532220, JP 2004530729, JP2004525929, JP 2004525179, JP 2004522786, JP 2004521149, JP 2004503531,JP 2004315496, JP 2004244412, JP 2004043429, JP 2004035574, JP2004026820, JP 2004026678, JP 2004002368, JP 2004002367, JP 2003535898,JP 2003535034, JP 2003531204, JP 2003531191, JP 2003531118, JP2003524591, JP 2003520849, JP 2003327532, JP 2003300977, JP 2003238566,JP 2002531547, JP 2002527504, JP 2002517401, JP 2002516318, JP2002363157, JP 2002356472, JP 2002356471, JP, 2002265439, JP 2001510442,JP 2000511559, JP 2000327689, JP 2000191616, JP 1998182613, JP1998081666, JP 1997509921, JP 1995501078, JP 1993508624, the disclosureof each of which is herein incorporated by reference in its entirety.

In one aspect of the present invention, the DPP-IV inhibitor isvaline-pyrrolidide (Deacon et al, Diabetes (1998) 47:764769; thedisclosure of which is herein incorporated by reference in itsentirety).

In one aspect of the present invention, the DPP-IV inhibitor is3-(L-Isoleucyl)thiazolidine (isoleucine-thiazolidide).Isoleucine-thiazolidide may be found in JP 2001510442, WO 97/40832, U.S.Pat. No. 6,303,661, and DE 19616486, the disclosure of each of which isherein incorporated by reference in its entirety.Isoleucine-thiazolidide is described as an orally active and selectiveDPP-IV inhibitor [Pederson et al, Diabetes (1998) 47:1253-1258; thedisclosure of which is herein incorporated by reference in itsentirety].

In one aspect of the present invention, the DPP-IV inhibitor is1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine(NVP-DPP728). NVP-DPP728 may be found in WO 98/19998 and JP 2000511559,the disclosure of each of which is herein incorporated by reference inits entirety. NVP-DPP728 is described as an orally active and selectiveDPP-IV inhibitor [Villhauer et al, J Med Chem (2002) 45:2362-2365].

In one aspect of the present invention, the DPP-IV inhibitor is3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one(MK-0431; sitagliptin). MK-0431 may be found in EP 1412357, WO 03/04498,U.S. Pat. No. 6,699,871, and US 2003100563, the disclosure of each ofwhich is herein incorporated by reference in its entirety. MK-0431 isdescribed as an orally active and selective DPP-IV inhibitor [Weber etal, Diabetes (2004) 53(Suppl. 2):A151, 633-P (Abstract), the disclosureof which is herein incorporated by reference in its entirety].

In one aspect of the present invention, the DPP-IV inhibitor is(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine(LAF237; vildagliptin). LAF237 may be found in U.S. Pat. No. 6,166,063,WO 00/34241, EP 1137635, and JP 2002531547, the disclosure of each ofwhich is herein incorporated by reference in its entirety. LAF237 isdescribed as an orally active and selective DPP-IV inhibitor [Villhaueret al, J Med Chem (2003) 46:2774-2789].

In one aspect of the present invention, the DPP-IV inhibitor is(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile(BMS-477118; saxagliptin).

In one aspect of the present invention, the DPP-IV inhibitor is[1-[2(S)-Amino-3-methylbutyryl]pyrrolidin-2(R)-yl]boronic acid (PT-100).

In one aspect of the present invention, the DPP-IV inhibitor isGSK-823093.

In one aspect of the present invention, the DPP-IV inhibitor isPSN-9301.

In one aspect of the present invention, the DPP-IV inhibitor is T-6666.

In one aspect of the present invention, the DPP-IV inhibitor is SYR-322(alogliptin).

In one aspect of the present invention, the DPP-IV inhibitor is SYR-619.

In one aspect of the present invention, the DPP-IV inhibitor isCR-14023.

In one aspect of the present invention, the DPP-IV inhibitor isCR-14025.

In one aspect of the present invention, the DPP-IV inhibitor isCR-14240.

In one aspect of the present invention, the DPP-IV inhibitor isCR-13651.

In one aspect of the present invention, the DPP-IV inhibitor isNNC-72-2138.

In one aspect of the present invention, the DPP-IV inhibitor is NN-7201.

In one aspect of the present invention, the DPP-IV inhibitor isPHX-1149.

In one aspect of the present invention, the DPP-IV inhibitor isPHX-1004.

In one aspect of the present invention, the DPP-IV inhibitor isSNT-189379.

In one aspect of the present invention, the DPP-IV inhibitor isGRC-8087.

In one aspect of the present invention, the DPP-IV inhibitor is PT-630.

In one aspect of the present invention, the DPP-IV inhibitor is SK-0403.

In one aspect of the present invention, the DPP-IV inhibitor isGSK-825964.

In one aspect of the present invention, the DPP-IV inhibitor is TS-021.

In one aspect of the present invention, the DPP-IV inhibitor isGRC-8200.

In one aspect of the present invention, the DPP-IV inhibitor isGRC-8116.

In one aspect of the present invention, the DPP-IV inhibitor isFE107542.

In one aspect of the present invention, the DPP-IV inhibitor is(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine.

In one aspect of the present invention, the DPP-IV inhibitor issitagliptin.

In one aspect of the present invention, the DPP-IV inhibitor is Januvia™(sitagliptin phosphate).

In one aspect of the present invention, the DPP-IV inhibitor is(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one.

In one aspect of the present invention, the DPP-IV inhibitor is selectedfrom the right column of Table D. It is expressly contemplated that eachindividual DPP-IV inhibitor from the right column of Table D is aseparate embodiment within the scope of the present invention.

In one aspect of the present invention, the DPP-IV inhibitor is selectedfrom any set of compounds selected from the right column of Table D.

In one aspect of the present invention, the DPP-IV inhibitor is acompound of Formula (XIX).

In one aspect of the present invention, the DPP-IV inhibitor is acompound of Formula (XX).

In one aspect of the present invention, the DPP-IV inhibitor is acompound of Formula (XXI).

In one aspect of the present invention, the DPP-IV inhibitor is acompound of Formula (XXII).

In one aspect of the present invention, the DPP-IV inhibitor is acompound selected from Group S1, Group T1, Group V1, or Group V2.

In one aspect of the present invention, the DPP-IV inhibitor isidentical to a compound disclosed in International Application No.PCT/US02/21349 (published as WO 03/004498).

In one aspect of the present invention, the DPP-IV inhibitor isidentical to a compound disclosed in International Application No.PCT/EP99/09708 (published as WO 00/34241).

In one aspect of the present invention, the DPP-IV inhibitor isidentical to a compound disclosed in International Application No.PCT/US01/07151 (published as WO 01/68603).

In one aspect of the present invention, the DPP-IV inhibitor isidentical to a compound disclosed in International Application No.PCT/US2004/042209 (published as WO 2005/095381).

In one aspect of the present invention, the DPP-IV inhibitor has an IC₅₀of less than about 10 μM, less than about 1 μM, less than about 100 nM,less than about 75 nM, less than about 50 nM, less than about 25 nM,less than about 20 nM, less than about 15 nM, less than about 10 nM,less than about 5 nM, less than about 4 nM, less than about 3 nM, lessthan about 2 nM, or less than about 1 nM. In certain embodiments, theDPP-IV inhibitor has an IC₅₀ of less than about 50 nM, less than about25 nM, less than about 20 nM, less than about 15 nM, less than about 10nM, less than about 5 nM, less than about 4 nM, less than about 3 nM,less than about 2 nM, or less than about 1 nM.

In one aspect of the present invention, the DPP-IV inhibitor is aselective DPP-IV inhibitor, wherein the selective DPP-IV inhibitor has aselectivity for human plasma DPP-IV over one or more of PPCE, DPP-II,DPP-8 and DPP-9 of at least about 10-fold, and in particular embodimentof at least about 100-fold, and in further particular embodiment of atleast about 1000-fold.

In one aspect of the present invention, the DPP-IV inhibitor is a smallmolecule.

In one aspect of the present invention, the DPP-IV inhibitor is orallyactive.

In one aspect of the present invention, the DPP-IV inhibitor is aninhibitor of human DPP-IV.

In one aspect of the present invention, any one or more DPP-IV inhibitorcan be excluded from any embodiment of the present invention.

Combination of GPR119 Agonist and DPP-IV Inhibitor

By way of illustration and not limitation, an exemplary combination ofGPR119 agonist and DPP-IV inhibitor in accordance with the presentinvention is provided by selecting a GPR119 agonist from the left columnof Table D and a DPP-IV inhibitor from the right column of Table D. Itis expressly contemplated that each individual combination of GPR119agonist and DPP-IV inhibitor provided by selecting a GPR119 agonist fromthe left column of Table D and a DPP-IV inhibitor from the right columnof Table D is a separate embodiment within the scope of the presentinvention.

TABLE D GPR119 Agonist DPP-IV Inhibitor[6-(4-Benzenesulfonyl-piperidin-1-yl)- valine-pyrrolidide5-nitro-pyrimidin-4-yl]-(4- methanesulfonyl-phenyl)-amine{4-[6-(4-Methanesulfonyl- 3-(L-Isoleucyl)thiazolidinephenylamino)-5-nitro-pyrimidin-4-yl]- (isoleucine-thiazolidide)piperazin-1-yl}-acetic acid ethyl ester(2-Fluoro-4-methanesulfonyl-phenyl)-1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5- pyrrolidineyl)-piperidin-1-yl]-5-nitro-pyrimidin-4- (NVP-DPP728) yl)-amine6′-[4-(2-Methoxycarbonyl-acetyl)-3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-phenoxy]-3-nitro-3,4,5,6-terahydro-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-2H-[1,2′]bipyridinyl-4-carboxylic acid trifluorophenyl)butan-1-one ethylester (MK-0431; sitagliptin) 1-[4-(4-Acetyl-3′-nitro-3,4,5,6-(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidintetrahydro-2H-[1,2′]bipyridinyl -6′- (LAF237; vildagliptin)yloxy)-phenyl]-ethanone 6′-[4-(4-Hydroxy-benzenesulfonyl)-(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2-phenoxy]-3-nitro-3 4,5,6-tetrahydro-azabicyclo[3.1.0]hexane-3-carbonitrile 2H-[1,2′]bipyridinyl-4-carboxylicacid (BMS-477118; saxagliptin) ethyl ester1-[5-(4-Benzoyl-phenoxy)-2-nitro-[1-[2(S)-Amino-3-methylbutyryl]pyrrolidin-2(R)-yl]boronic acidphenyl]-piperidine-4-carboxylic acid (PT-100) ethyl ester1-[5-[4-(2-Methoxycarbonyl-acetyl)- GSK-823093phenoxy]-2-nitro-phenyl)-piperidine-4- carboxylic acid ethyl ester1-[5-(2-Amino-4-ethanesulfonyl- PSN-9301phenoxy)-2-nitro-phenyl)-piperidine-4- carboxylic acid ethyl ester5-Bromo-1-[4-nitro-3-(4-propyl- T-6666piperidin-1-yl)-phenyl]-1H-pyridin-2- one6′-Benzenesulfonylamino-3′-nitro- SYR-3223,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl- (alogliptin) 4-carboxylic acidethyl ester 6′-(Benzenesulfonyl-methyl-amino)-3′- SYR-619nitro-3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl-4-carboxylic acid ethylester 6′-(Benzenesulfonyl-butyl-amino)-3- CR-14023nitro-3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl-4-carboxylic acid ethylester 1-[5-(4-Benzoyl-phenylamino)-2-nitro- CR-14025phenyl]-piperidine-4-carboxylic acid ethyl ester{4-[4-Nitro-3-(4-propyl-piperidin-1-yl)- CR-14240phenylamino)-phenyl}-phenyl- methanone 3-[6-(4-Mehanesulfonyl- CR-13651phenylamino)-5-nitro-pyrimidin-4- yloxymethyl]-pyrrolidine-1-carboxylicacid tert-butyl ester 4-[5-Cyano-6-(6-methylsulfanyl- NNC-72-2138pyridin-3-ylamino)-pyrimidin-4-yloxy) piperidine-1-carboxylic acidtert-butyl ester 4-[5-Cyano-6-(6-methanesulfonyl- NN-7201pyridin-3-ylamino)-pyrimidin-4-yloxy]- piperidine-1-carboxylic acidtert-butyl ester 4-[6-(4-Methanesulfonyl- PHX-1149phenylamino)-5-nitro-pyrimidin-4- yloxyl-piperidine-1-carboxylic acidtert-butyl ester (4-Methanesulfonyl-phenyl)-[5-nitro-6- PHX-1004(piperidin-4-yloxy)-pyrimidin-4-yl]- amine 1-{4-[6-(4-Methanesulfonyl-SNT-189379 phenylamino)-5-nitro-pyrimidin-4-yloxy]-piperidin-1-yl}-3,3-dimethy]- butan-1-one4-[6-(4-Methanesulfonyl- GRC-8087 phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidine-1-carboxylic acid tert-butyl esterN-(4-Methanesulfonyl-phenyl)-5-nitro- PT-630N′-piperidin-4-yl-pyrimidine-4,6- diamine 1-{4-[6-(4-Methanesulfonyl-SK-0403 phenylamino)-5-nitro-pyrimidin-4-ylamino]-piperidin-1-yl}-ethanone 4-[6-(4-Cyano-2-fluoro-phenylamino)-GSK-825964 5-ethynyl-pyrimidin-4-yloxy]- piperidine-1-carboxylic acidisopropyl ester 4-[5-Ethynyl-6-(2-fluoro-4-8-(3-Aminopiperidin-1-yl)-N2,7-dibenzyl-1-methylguanine[1,2,4]triazol-1-yl-phenylamino)- trifluoroacetatepyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester4-{5-Ethynyl-6-[1-(3-isopropyl-N-[2-[2-[8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-3-methylxanthir[1,2,4]oxadiazol-5-yl)-piperidin-4- 1-yl]acetyl]phenyl]formamideyloxy]-pyrimidin-4-ylamino}-3-fluoro- benzonitrile4-[5-Acetyl-6-(6-methanesulfonyl-8-[3(R)-Aminopiperidin-1-yl]-7-(2-butynyl)-3-methyl-1-pyridin-3-ylamino)-pyrimidin-4-yloxy]- (quinazolin-2-ylmethyl)xanthinepiperidine-1-carboxylic acid isobutyl ester1-[4-(1-Benzyl-azetidin-3-yloxy)-6-(6-8-(3-Aminopiperidin-1-yl)-1-(benzo[c]-1,8-naphthyridin-6-methanesulfonyl-pyridin-3-ylamino)-ylmethyl)-7-(2-butynyl)-3-methylxanthine pyrimidin-5-yl]-ethanone4-[5-Cyano-6-(6-propylamino-pyridin-2-[8-[3(R)-Aminopiperidin-1-yl]-7-(2-butynyl)-3-methylxanthin-1-3-ylamino)-pyrimidin-4-yloxy]- yl]-N-(2-pyridyl)acetamidepiperidine-1-carboxylic acid isopropyl ester4-(2-Fluoro-4-methanesulfonyl-2-(3-Aminopiperidin-1-yl)-3-(2-butynyl)-5-(quinoxalin-6-ylmethyl;phenylamino)-5-methyl-pyrimidin-4-4,5-dihydro-3H-imidazo[4,5-d]pyridazin-4-oneyl]-isopropyl-amino}-methyl)- piperidine-1-carboxylic acid tert-butylester 4-(2-Fluoro-4-methanesulfonyl- (1S, 3S,5S)-2-[2(S)-Amino-4,4-dimethyl pentanoyl]-2-phenoxy)-6-[1-(3-methoxy-propyl)-azabicyclo[3.1.0]hexane-3(S)-carbonitrile trifluoroacetatepiperidin-4-yloxy]-5-methyl-pyrimidine1-{4-[6-(2-Fluoro-4-methanesulfonyl-N1-(1-Cyanoethyl)-N1,3-dimethyl-L-valinamidephenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidin-1-yl]-3-methoxy-propan-2-ol4-{6-[2-Fluoro-4-(5-isopropoxymethyl- (1S, 3S,5S)-2-[2(S)-Amino-2-[1-(3,3-dimethylbuyryl)piperidin-4-[1,2,4]oxadiazol-3-yl)-phenoxy]-5-yl]acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrilemethyl-pyrimidin-4-yloxy)-piperidine- 1-carboxlic acid isopropyl ester4-[6-(2-Fluoro-4-morpholin-4-yl-2-[7-(2-Butynyl)-1-(2-phenylethyl)-8-(1-piperazinyl)xanthin-3-yl]-phenoxy)-5-methyl-pyrimidin-4-yloxy]- N-(2-propynyl)acetamidehydrochloride piperidine-1-carboxylic acid isopropyl ester{4-[6-(2-Fluoro-4-methanesulfonyl-2-[7-(2-Butynyl)-1-(3-cyanobenzyl)-6-oxo-8-(1-piperazinyl)-6,7-phenoxy)-5-methyl-pyrimidin-4-yloxy]-dihydro-1H-purin-2-yloxy]-N-methylbenzamide trifluoroacetatepiperidin-1-yl}-[6-(2-pyrrolidin-1-yl- ethyl)-pyridin-3-yl]-methanone(6-Amino-pyridin-3-yl)-{4-[6-(2-2-[3-(2-Butynyl)-4-oxo-2-(1-piperazinyl)-4,5-dihydro-3H-fluoro-4-methanesulfonyl-phenoxy)-5-imidazo[4,5-d]pyridazin-5-ylmethyl]benzonitrile trifluoroacetatemethyl-pyrimidin-4-yloxy]-piperidin-1- yl}-methanone4-({Cyclopropyl-[6-(2-fluoro-4-N-[1(S)-[2(S)-Cyanopyrrolidin-1-ylcarbonyl]-4-(pyrazin-2-methanesulfonyl-phenoxy)-5-methyl- ylcarboxamido)butyl]carbamic acid1-acetoxyethyl ester pyrimidin-4-yl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester4-({Cyclopropyl-[6-(2-fluoro-4-2(S),4-Diamino-1-(4-thiomorpholinyl)butan-1-onemethanesulfonyl-phenoxy)-5-methyl- pyrimidin-4-yl]-amino)-methyl)-piperidine-1-carboxylic acid isopropyl ester4-({[6-(2-Fluoro-4-methanesulfonyl-1-[Perhydroindol-2(S)-ylcarbonyl]azetidine-2(S)-carbonitrilephenoxy)-5-methyl-pyrimidin-4-yl]-isopropyl-amino}-methyl)-piperidine-1- carboxytic acid isopropyl ester4-[6-(2-Fluoro-4-methanesulfonyl- 1-(2-Benzothiazolyl)-1-[1-[(2S, 3aS,7aS)-perhydroindol-2- phenylamino)-5-methyl-pyrimidin-4-ylcarbonyl]pyrrolidin-2(S)-yl]methanone hydrochlorideylsulfanyl]-piperidine-1-carboxylic acid isopropyl ester4-[1-(4-Methanesulfonyl-phenyl)-1H-1-[2(S)-Amino-2-cyclohexylacetyl]-4-methylazetidine-2-carbonitrilpyrazolo[3,4-d]pyrimidin-4-yloxy]- hydrochloride piperidine-1-carboxylicacid tert-butyl ester 4-[1-(4-Methanesulfonyl-phenyl)-3-6-[2-[2-[5(S)-Cyano-4,5-dihydro-1H-pyrazol-1-yl]-2-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-oxoethylamino]ethylamino]pyridine-3-carbonitrileyloxy]-piperidine-1-carboxylic acid tert-butyl ester4-[1-(4-Mechanesulfonyl-phenyl)-3,6-6-[2-[2-[2(S)-Cyano-4(S)-fluoropyrrolidin-1-yl]-2-oxoethylamino]dimethyl-1H-pyrazolo[3,4-d]pyrimidin-2-methylpropylamino]-N,N-dimethylpyridine-3-sulfonamide4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester4-({[1-(2,5-Difluoro-phenyl)-1H-trans-N-[4-[1(S)-Amino-2-[3(S)-fluoropyrrolidin-1-yl]-2-pyrazolo[3,4-d]pyrimidin-4-yl]-methyl-oxoethyl]cyclohexyl]-2,4-difluorobenzenesulfonamideamino)-methyl)-piperidine-1- carboxylic acid tert-butyl ester2-{4-[1-(2-Fluoro-4-methanesulfonyl-2(S)-Amino-1-(1-pyrrolidinyl)-2-(4-(thiazol-2-phenyl)-1H-pyrazolo[3,4-d]pyrimidin- ylamino)cyclohexyl]ethanonetrifluoroacetate 4-yloxy]-piperidin-1-yl}-1-(4-trifluoromethoxy-phenyl)-ethanone 2-{4-[1-(2-Fluoro-4-methanesulfonyl-N-[(1R,3R)-3-[1(S)-Amino-2-oxo-2-(1-phenyl)-1H-pyrazolo[3,4-d]pyrimidin- pyrrolidinyl)ethyl]cyclopentyl]-4-4-yloxy]-piperidin-1-yl}-1-(3-fluoro- (methylsulfonyl)benzenesulfonamidephenyl)-ethanone 4-[9-(6-Methanesulfonyl-pyridin-3-yl)-3(R)-Amino-1-(6-benzyl-3-methyl-5,6,7,8-tetrahydroimidazo[1,2-9H-purin-6-yloxy]-piperidine-1-a]pyrazin-7-yl)-4-(3,4-difluorophenyl)butan-1-one carboxylic acidisobutyl ester (4-[9-(6-Methanesulfonyl-pyridin-3-trans-N-[4-[1(S)-Amino-2-oxo-2-(1-pyrrolidinyl)ethyl]cyclohexyl]-yl)-9H-purin-6-yloxy]-piperidin-1-yl}- 2,4-difluorobenzenesulfonamidepyridin-3-yl-methanone 4-[9-(4-Methanesulfonyl-phenyl)-9H-3(R)-Amino-4-(2,5-difluorophenyl)-1-[4-hydroxy-2-purin-6-yloxy)-piperidine-1-carboxylic(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7- acidtert-butyl ester yl]butan-1-one 4-[9-(2-Fluoro-4-propionylsulfamoyl-N-[(1R,3R)-3-[1(S)-Amino-2-oxo-2-(1-phenyl)-9H-purin-6-yloxy]-piperidine- pyrrolidinyl)ethyl]cyclopentyl]-2-1-carboxylic acid isopropyl ester (methylsulfonamido)ethanesulfonamide4-[9-(4-Cyano-2-fluoro-phenyl)-9H-2-[4-[3(R)-Amino-4-(2-fluorophenyl)butyryl]-3(R)-benzylpiperazinpurin-6-yloxy)-piperidine-1-carboxylic1-yl]-N-[3-(methylsulfonamido)phenyl]acetamide acid isopropyl ester4-[9-(2-Fluoro-4-sulfamoyl-phenyl)-3(R)-Amino-1-(3-thiazolidinyl)-4-(2,4,5-trifluorophenyl)butan-1-9H-purin-6-yloxy]-piperidine-1- one carboxylic acid isopropyl ester4-[3-(4-Methanesulfonyl-phenyl)-3H-4-[3(R)-Amino-4-(2,4,5-trifluorophenyl)butyryl]-3(R)-methyl-1,4-[1,2,3]triazolo[4,5-d]pyrimidin-7- diazepan-2-oneyloxy]-piperidine-1-carboxylic acid tert-butyl ester3-(2-Fluoro-4-methanesulfonyl-3(S)-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-phenyl)-7-[1-(3-isopropyl-2(S)-[4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)phenyl]butyramide[1,2,4]oxadiazol-5-yl)-piperidin-4- yloxy]-3H-[1,2,3]triazolo[4,5-d]pyrimidine 3-Fluoro-4-{7-[1-(3-isopropyl-3(R)-Amino-1-[2-(trifluoromethyl)-5,6,7,8-[1,2,4]oxadiazol-5-yl)-piperidin-4-tetrahydro[1,2,4]triazolo[1,5-a]pyrazine-7-yl]-4-(2,4,5-yloxy]-[1,2,3]triazolo[4,5-d]pyrimidin- trifluorophenyl)butanonehydrochloride 3-yl}-N-propionyl-benzenesulfonamide3-Fluoro-4-{7-[1-(3-isopropyl-2(S)-Amino-3(S)-(4-fluorophenyl)-1-(3-thiazolidinyl)butan-1-one[1,2,4]oxadiazol-5-yl)-piperidin-4-yloxyl-(1,2,3]triazolo[4,5-d]pyrimidin- 3-yl}-benzonitrile4-[3-(4-Methanesulfonyl-phenyl)-7-[3(R)-Amino-4-(2,5-difluorophenyl)butyryl]-5,6,7,8-isoxazolo[4,5-d]pyrimidin-7-yloxy]-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl esterpiperidine-1-carboxylic acid tert-butyl ester4-({Ethyl-[3-(4-methanesulfonyl-3(R)-Amino-1-(8-chloro-1,2,3,4-tetrahydropyrazino[1,2-phenyl)-isoxazolo[4,5-d]pyrimidin-7-a]benzimidazol-2-yl)-4-(2,5-difluorophenyl)butan-1-oneyl]-amino}-methyl)-piperidine-1- trifluoroacetate carboxylic acidtert-butyl ester 4-[3-(4-Methanesulfonyl-phenyl)-3(R)-Amino-4-(2,5-difluorophenyl)-1-[2-(4-fluorophenyl)-4,5,6,7-isoxazolo[4,5-d]pyrimidin-7-tetrahydrothiazolo[4,5-c]pyridin-5-yl]buttan-1-oneylsulfanyl]-piperidine-1-carboxylic acid tert-butyl ester4-[3-(4-Methanesulfonyl-phenyl)-2-[4-[2-[3(R)-Amino-4-(2-fluorophenyl)butyryl]-1,2,3,4-isoxazolo[4,5-d]pyrimidin-7-yloxy]-tetrahydroisoquinolin-3-ylcarboxamidomethyl]phenyl]acetic acidpiperidine-1-carboxylic acid isopropyl ester4-[8-(2-Fluoro-4-methanesulfonyl-3(S)-Amino-2-oxopiperidin-1-ylphosphonic diamide hydrochloridephenyl)-[1,7]naphthyridin-4-yloxy]- piperidine-1-carboxylic acidisopropyl ester 4-[8-(2-Fluoro-4-methanesulfonyl-2-[2-(5-Nitropyridin-2-ylamino)ethylamino]-1-(1-phenyl)-quinolin-4-yloxy]-piperidine-1- pyrrolidinyl)ehanonedihydrochloride carboxylic acid isopropyl ester4-[8-(4-Methylsulfanyl-phenyl)-2-[8-(3-Aminopiperidin-1-yl)-1,3-dimethylxanthin-7-quinolin-4-yloxy]-piperidine-1- ylmethyl]benzonitrile hemisuccinatecarboxylic acid isopropyl ester 4-[8-(4-Methanesulfonyl-phenyl)-2(S)-Amino-2-cyclohexyl-1-(3,3,4,4-tetrafluoropyrrolidin-1-quiriolin-4-yloxy]-piperidine-1- yl)ethanone hydrochloride carboxylicacid isopropyl ester 4-[8-(2-Fluoro-4-methanesulfonyl-2(S)-Amino-2-cyclohexyl-1-(3-fluoropyrrolidin-1-yl)ethanonephenyl)-pyrido[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acidisopropyl ester 4-[8-(2-Fluoro-4-propionylsulfamoyl-2-Amino-1-cyclopentyl-3-methylpentan-1-one hydrochloridephenyl)-pyrido[3,4-d]pyrimidin-4- yloxy]-piperidine-1-carboxylic acidisopropyl ester 4-[8-(4-Cyano-2-fluoro-phenyl)-4-Amino-5-oxo-5-(1-pyrrolidinyl)pentanamidepyridol[3,4-d]pyrimidin-4-yloxy]- piperidine-1-carboxylic acid isopropylester 3-(2-Fluoro-4-methanesuifonyl-1-[2-[1,1-Dimethyl-2-(6-phenylpyridin-2- phenyl)-7-(4-(3-isopropyl-ylamino]ethylamino]acetyl]pyrrolidine-2(S)-carbonitrile[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]- hydrochloridepyrazolo[1,5-a]pyrimidine 3-Fluoro-4-(7-[4-(3-isopropyl-(7R*,8S*,13bS*)-7-Butyl-11,12-dimethoxy-,3,4,4a,6,7,8,9,9a,13b-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]-decahydro-1H-pyrido[1,2-f]phenanthridin-8-aminepyrazolo[1,5-a]pyrimidin-3-yl}-N- propionyl-benzenesulfonamide3-Fluoro-4-(7-[4-(3-isopropyi-5-(Aminomehyl)-6-(2,4-dichlorophenyl)-2-(3,5-[1,2,4]oxadiazol-5-yl)-cyclohexyloxy]- dimethoxyphenyl)pyrimidin-4-aminepyrazolo[1,5-a]pyrimidin-3-yl}- benzonitrile4-[3-(2-Fluoro-4-methanesulfonyl-3-(Aminomethyl)-4-(2,4-dichlorophenyl)-7,8-dimethoxy-5H-phenyl)-1-methyl-1H-pyrazolo[4,3- indeno(1,2-b]pyridin-2-amined]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester4-[3-(2-Fluoro-4-propionylsulfamoyl-5-(Aminomethyl)-6-(2,4-dichlorophenyl)-N2-(2-methoxyethyl)-N2phenyl)-1-methyl-1H-pyrazolo[4,3- methylpyrimidine-2,4-diamined]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester4-[3-(4-Cyano-2-fluoro-phenyl)-1-4,4-Difluoro-1-[2-[exo-8-(2-pyrimidinyl)-8-azabicyclo[3.2.1]oct-3methyl-1H-pyrazolo(4,3-d]pyrimidin-7-ylamino]acetyl]pyrrolidine-2(S)-carbonitrileyloxy]-piperidine-1-carboxylic acid isopropyl ester4-[3-(2-Fluoro-4-mehanesulfonyl-exo-3-[2-[8-(2-Pyrimidinyl)-8-azabicyclo[3.2.1]oct-3-phenyl)-2-methyl-2H-pyrazolo[4,3-ylamino]acetyl]thiazolidine-4(R)-carbonitrile.d]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester4-[3-(2-Fluoro-4-propionylsulfamoyl- 1-[2-[3-(2,3-Dihydro-1H-isoindol-2-yl)-1,1-dimethyl-3-phenyl)-2-methyl-2H-pyrazolo[4,3-oxopropylamino]acetyl]pyrrolidine-2(S)-carbonitriled]pyrimidin-7-yloxy]-piperidine-1- carboxylic acid isopropyl ester4-[3-(4-Cyano-2-fluoro-phenyl)-2-8-(3-Aminoperhydroazepin-1-yl)-3-methyl-7-(2-methylbenzyl)-methyl-2H-pyrazolo[4,3-d]pyrimidin-7-2,3,6,7-tetrahydro-1H-purine-2,6-dione yloxy]-piperidine-1-carboxylicacid isopropyl ester 4-[4-(3-Isopropyl-[1,2,4]oxadiazol-5-8-[3(R)-Aminopiperidin-1-yl]-7-(5-fluoro-2-methylbenzyl)-1,3-yl)-piperidin-1-yl]-6-(4- dimethylxanthinemehanesulfonyl-phenoxy)-pyrimidine {6-[4-(3-Isopropyl-[1,2,4]oxadiazo-5-2-[2-(3-Aminopiperidin-1-yl)-6,7-dimethoxy-4-oxo-3,4-yl)-piperidin-1-yl]-pyrimidin-4-yl)-(4-dihydroquinazolin-3-ylmethyl]benzonitrile methanesulfonyl-phenyl)-amine4-{[6-(2-Fluoro-4-methanesulfonyl- 1 -[2(S)-Amino-3,3-dimethylbutyryl]-4(S)-fluoropyrrolidine-2(S)-phenylamino)-pyrimidin-4-yl]-methyl- carbonitrile hydrochlorideamino)-piperidine-]-carboxylic acid tert-butyl ester4-[6-(2-Fluoro-4-methanesulfonyl- 2-[3-(Aminomethyl)-4-butoxy-2-(2,2-dimethylpropyl)-1-oxo-1,2-phenylamino)-pyrimidin-4-yloxy]- dihydroisoquinolin-6-yloxy]acecamidehydrochloride piperidine-1-carboxylic acid tert-butyl ester(2-Fluoro-4-methanesulfonyl-phenyl)-3-(3-Chloroimidazo[1,2-a]pyridin-2-ylmethylsulfonyl)-N,N-(6-[1-(3-isopropyl-[1,2,4]oxadiazol-5-dimethyl-1H-1,2,4-triazole-1-carboxamide ylmethyl)-piperidin-4-yloxy]-pyrimidin-4-yl}-amine; 4-[6-(2-Fluoro- 4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester(6-Chloro-pyridin-2-yl)-{4-[6-(2-6-Chloro-2-isobutyl-4-phenylquinolin-3-ylmethylaminefluoro-4-methanesulfonyl- phenylamino)-pyrimidin-4-yloxy]-piperidin-1-yl}-methanone [2-(4-Bromo-phenyl)-6-methyl-trans-1-[2-[4-(1,3-Dioxo-2,3-dihydro-1H-isoindol-2-pyrimidin-4-yl]-methyl-amineyl)cyclohexylamino]acetyl]pyrrolidine-2(S)-carbonitrile hydrochloride[2-(4-Bromo-phenyl)-6-methyl-trans-4-[2-[4(R)-Cyanothiazolidin-3-yl]-2-oxoethylamino]-N,N-pyrimidin-4-yl]-p-tolyl-amine dimethylcyclohexanecarboxamidehydrochloride [2-(4-Bromo-phenyl)-6-methyl-N-(5-Chloropyridin-2-yl)-2-[4-[1-[2-(4-cyanothiazolidin-3-yl)-2-pyrimidin-4-yl]-(4-methoxy-phenyl)-oxoethyl]hydrazino]piperidin-1-yl]acetamide tris(trifluoroacetate) amine[2-(4-Bromo-phenyl)-6-methyl- 6-[2-[2-[2(S)-Cyanoazetidin-1-yl]-2-pyrimidin-4-yl]-phenyl-amineoxoethylamino]ethylamino]pyridine-3-carbonicrile dihydrochloride[2-(4-Bromo-phenyl)-6-methyl-4(S)-Fluoro-1-[2-[1-(2-hydroxyacetyl)-4-methylpiperidin-4-pyrimidin-4-yl]-cyclohexyl-amineylamino]acetyl]pyrrolidine-2(S)-carbonitrile fumarate5-[2-(4-Bromo-phenyl)-6-ethyl- TS-021 pyrimidin-4-ylamino]-pentan-1-ol3-[2-(4-Bromo-phenyl)-6-methyl- GRC-8200pyrimidin-4-ylamino]-propionitrile [2-(4-Bromo-phenyl)-6-ethyl- GRC-8116pyrimidin-4-yl]-(4-fluoro-benzyl)- amine [2-(4-Bromo-phenyl)-6-ethyl-FE107542 pyrimidin-4-yl]-[2-(4-chloro-phenyl)- ethyl]-amine[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-yl]-pyridin-2-ylmethyl- amine

(2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-pyridin-3-ylmethyl- amine

3-{[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-ylamino]-methyl}-1H-pyridin-2-one

4-{[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-ylamino]-methyl}-1H-pyridin-2-one

4-{2-[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-ylamino]-ethyl-1H-pyridin-2-one

[2-(3-Chloro-4-fluoro-phenyl)-6-ethyl-pyrimidin-4-yl]-(1,1-dioxo-hexahydro- 116-thiopyran-4-yl)-amine

[6-Methyl-2-(3,4,5-trifiuoro-phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3- yl)-ethyl]-amine

[6-Ethyl-2-(3,4,5-trifluoro-phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3- yl)-ethyl]-amine

[6-Methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-yl]-[2-(1-oxy-pyridin-3- yl)-ethyl]-amine

4-{4-Methyl-6-[2-(1-oxy-pyridin-3-yl)- ethylamino]-pyrimidin-2-yl}-benzonitrile

2-[4-(6-Methyl-2-phenyl-pyrimidin-4- ylamino)-phenyl]-ethanol

[2-(3-Chloro-phenyl)-6-methyl- pyrimidin-4-yl]-methyl-amine

2-{[2-(4-Bromo-phenyl)-6-methyl- pyrimidin-4-yl]-methyl-amino}- ethanol;compound with methane

3-[6-Ethyl-2-(3,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol

(S)-3-[6-Methyl-2-(2,3,5-trifluoro-phenyl)-pyrimidin-4-ylamino]-propane- 1,2-diol

(S)-3-[2-(4-Bromo-3-fluoro-phenyl)-6-methyl-pyrimidin-4-ylamino]-propane- 1,2-diol

(R)-3-[6-Ethyl-2-(3,4,5-trifluoro- phenyl)-pyrimidin-4-ylamino]-propane-1,2-diol

(R)-3-[2-(3-Chloro-4-fluoro-phenyl)-6-ethyl-pyrimidin-4-ylamino]-propane- 1,2-diol

(R)-3-[2-(4-Bromo-2,5-difluoro- phenyl)-5-fluoro-6-methyl-pyrimidin-4-ylamino]-propane-1,2-diol

(R)-3-[2-(4-Chloro-2,5-difluoro- phenyl)-6-difluoromethyl-pyrimidin-4-ylamino]-propane-1,2-diol

5-{2-[2-(4-Bromo-phenyl)-6-ethyl- pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one

5-{2-[6-Methyl-2-(2,4,5-trifluoro- phenyl)-pyrimidin-4-ylamino]-ethyl}-1H-pyridin-2-one

4-{2-[2-(4-Chloro-2,5-difluoro-phenyl)-6-ethyl-pyrimidin-4-ylamino]-ethyl}- 1H-pyridin-2-one

6-Chloro-4-{2-[6-methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]- ethyl}-1H-pyridin-2-one

4-{1-Hydroxy-2-[6-methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]- ethyl}-1H-pyridin-2-one

4-{1-Methyl-2-[6-methyl-2-(2,4,5-trifluoro-phenyl)-pyrimidin-4-ylamino]- ethyl}-1H-pyridin-2-one

4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5- ylmethoxy)piperidine-1-carboxylicacid tert-butyl ester

4-[5-(2-Cyanopyridin-4-yl)- [1,2,4]oxadiazol-3-ylmethoxy]piperidine-1-carboxylic acid tert-butyl ester

4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5- ylmethoxy)piperidine-1-carboxylicacid cyclopentyl ester

4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5- ylmethoxy)piperidine-1-carboxylicacid 2,2,2-trichloroethyl ester

4-[Ethyl-(3-pyridin-4-yl- [1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1- carboxylic acid tert-butyl ester

4-[Methyl-(3-pyridin-4-yl- [1,2,4]oxadiazol-5-ylmethyl)amino]piperidine-1- carboxylic acid cyclopentyl ester

4-{[Methyl-(3-pyridin-4-yl- [1,2,4]oxadiazol-5-ylmethyl)amino]methyl{piperidine-1- carboxylic acid 2,2,2-trichloroethylester

4-[5-(4-Butyl-cyclohexyl)- [1,2,4]oxadiazol-3-yl)-pyridine (PSN375963)

4-(3-Pyridin-4-yl-[1,2,4]oxadiazol-5- ylmethoxy)-piperidine-1-carboxylicacid tert-butyl ester (PSN632408)

4-[6-(6-Methanesulfonyl-2-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester

{6-[1-(3-Isopropyl-[1,2,4]oxadiazol-5- yl)-piperidin-4-yloxy]-5-methoxy-pyrimidin-4-yl}-(6-methanesulfonyl-2- methyl-pyridin-3-yl)-amine

4-[6-(6-Methanesulfonyl-4-methyl- pyridin-3-ylamino)-5-methoxy-pyrimidin-4-yloxy]-piperidine-1- carboxylic acid isopropyl ester

4-{[Methyl-(2-pyridin-4-ylpyrimidin-4- yl)-amino]methyl}piperidine-1-carboxylic acid tert-butyl ester

4-{[Methyl-(2-pyridin-4-ylpyrimidin-4-ylmethyl)amino]methyl}piperidine-1- carboxylic acid tert-butyl ester

4-[([2,4′]Bipyridinyl-6- ylmethylmethylamino)methyl]piperidine-1-carboxylic acid tert-butyl ester

(2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-A]pyrazin-7(8H)-yl]-1-(2,4,5-trifluoropbenyl)butan-2-amine(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one

Additionally, compounds of the invention, including those illustrated inTable D, encompass all pharmaceutically acceptable salts, solvates, andhydrates thereof. See, e.g., Berge et al (1977), Journal ofPharmaceutical Sciences 66:1-19; and Polymorphism in PharmaceuticalSolids (1999) Brittain, ed., Marcel Dekker, Inc.; the disclosure of eachof which is herein incorporated by reference in its entirety.

Composition/Formulation and Methods of Treatment

A GPR119 agonist optionally in combination with a DPP-IV inhibitoraccording to the present invention and including the combination therapyrelating to a GPR119 agonist in combination with a DPP-IV inhibitordescribed above can be formulated into pharmaceutical compositions andmedicaments for use in accordance with the present invention usingtechniques well known in the art. Proper formulation is dependent on theroute of administration chosen.

As relates to therapies of the present invention, namely therapiesrelating to a GPR119 agonist optionally in combination with a DPP-IVinhibitor and including the combination therapy relating to a GPR119agonist and a DPP-IV inhibitor described above, the compounds accordingto the invention can be administered in any suitable way. Suitableroutes of administration include oral, nasal, rectal, transmucosal,transdermal, or intestinal administration, parenteral delivery,including intramuscular, subcutaneous, intramedullary injections, aswell as intrathecal, direct intraventricular, intravenous,intraperitoneal, intranasal, intrapulmonary (inhaled) or intraocularinjections using methods known in the art. Other suitable routes ofadministration are aerosol and depot formulation. Sustained releaseformulations, particularly depot, of the invented medicaments areexpressly contemplated. In certain preferred embodiments, the compoundsaccording to the present invention are administered orally. Thecompounds according to the present invention can be made up in solid orliquid form, such as tablets, capsules, powders, syrups, elixirs and thelike, aerosols, sterile solutions, suspensions or emulsions, and thelike. In certain embodiments, one or both of the GPR119 agonist and theDPP-IV inhibitor are administered orally.

Formulations for oral administration may be in the form of aqueoussolutions and suspensions, in addition to solid tablet and capsuleformulations. The aqueous solutions and suspensions may be prepared fromsterile powders or granules. The compounds may be dissolved in water,polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseedoil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/orvarious buffers. Other adjuvants are well and widely known in the art.

It will be appreciated that the GPR119 agonist and the DPP-IV inhibitormay be present as a combined preparation for simultaneous, separate orsequential use for the treatment or prevention of a conditioncharacterized by low bone mass, such as osteoporosis, and for increasingbone mass in an individual. Such combined preparations may be, forexample, in the form of a twin pack.

It will therefore be further appreciated that the invention contemplatesa product comprising or consisting essentially of a GPR119 agonist and aDPP-IV inhibitor as a combined preparation for simultaneous, separate orsequential use in the treatment or prevention of a conditioncharacterized by low bone mass, such as osteoporosis, and for increasingbone mass in an individual.

A combination of the present invention comprising or consistingessentially of a GPR119 agonist and a DPP-IV inhibitor can be preparedby mixing the GPR119 agonist and the DPP-IV inhibitor either alltogether or independently with a pharmaceutically acceptable carrier,excipient, binder, diluent, etc. as described herein, and administeringthe mixture or mixtures either orally or non-orally as a pharmaceuticalcomposition(s).

It will therefore be further appreciated that the GPR119 agonist and theDPP-IV inhibitor or pharmaceutical composition can be administered inseparate dosage forms or in a single dosage form.

It is further appreciated that when the GPR119 agonist and the DPP-IVinhibitor are in separate dosage forms, GPR119 agonist and DPP-IVinhibitor can be administered by different routes.

Pharmaceutical compositions of the GPR119 agonist and DPP-IV inhibitor,either individually or in combination, may be prepared by methods wellknown in the art, e.g., by means of conventional mixing, dissolving,granulation, dragee-making, levigating, emulsifying, encapsulating,entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in accordance with the presentinvention may be formulated in conventional manner using one or morephysiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Suitablepharmaceutically acceptable carriers are available to those in the art[see, e.g., Remington: The Science and Practice of Pharmacy, (Gennaro etal., eds.), 20^(th) Edition, 2000, Lippincott Williams & Wilkins; andHandbook of Pharmaceutical Excipients (Rowe et al., eds), 4^(th)Edition, 2003, Pharmaceutical Press; the disclosure of each of which isherein incorporated by reference in its entirety]. Proper formulation isdependent upon, the route of administration chosen. The term “carrier”material or “excipient” material herein means any substance, not itselfa therapeutic agent, used as a carrier and/or diluent and/or adjuvant,or vehicle for delivery of a therapeutic agent to a subject or added toa pharmaceutical composition to improve its handling or storageproperties or to permit or facilitate formation of a dose unit of thecomposition into a discrete article such as a capsule or tablet suitablefor oral administration. Excipients can include, by way of illustrationand not limitation, diluents, disintegrants, binding agents, adhesives,wetting agents, polymers, lubricants, glidants, substances added to maskor counteract a disagreeable taste or odor, flavors, dyes, fragrances,and substances added to improved appearance of the composition.Acceptable excipients include stearic acid, magnesium stearate,magnesium oxide, sodium and calcium salts of phosphoric and sulfuricacids, magnesium carbonate, talc, gelatin, acacia gum, sodium alginate,pectin, dextrin, mannitol, sorbitol, lactose, sucrose, starches,gelatin, cellulosic materials, such as cellulose esters of alkanoicacids and cellulose alkyl esters, low melting wax cocoa butter orpowder, polymers, such as polyvinyl-pyrrolidone, polyvinyl alcohol, andpolyethylene glycols, and other pharmaceutically acceptable materials.The components of the pharmaceutical composition can be encapsulated ortableted for convenient administration.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

As relates to the combination therapy described above, when the GPR119agonist and the DPP-IV inhibitor are in separate dosage forms, it isunderstood that a pharmaceutically acceptable carrier used for theGPR119 agonist formulation need not be identical to a pharmaceuticallyacceptable carrier used for the DPP-IV inhibitor formulation.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used which may optionally containgum Arabic, talc; polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical compositions which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with a fillersuch as lactose, a binder such as starch, and/or a lubricant such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, liquid, polyethyleneglycols, cremophor, capmul, medium or long chain mono-, di- ortriglycerides. Stabilizers may be added in these formulations, also.

Additionally, a GPR119 agonist and the combination of a GPR119 agonistwith a DPP-IV inhibitor may be delivered using a sustained-releasesystem. Various sustained-release materials have been established andare well known to those skilled in the art. Sustained-release tablets orcapsules are particularly preferred. For example, a time delay materialsuch as glyceryl monostearate or glyceryl distearate may be employed.The dosage form may also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108, 4,166,452, and 4,265,874 to form osmotictherapeutic tablets for controlled release.

It is expressly contemplated that therapies of the present invention,namely therapies relating to a GPR119 agonist optionally in combinationwith a DPP-IV inhibitor and including the combination therapy relatingto a GPR119 agonist and a DPP-IV inhibitor described above, may beadministered or provided alone or in combination with one or more otherpharmaceutically or physiologically acceptable compound. In one aspectof the present invention, the other pharmaceutically or physiologicallyacceptable compound is not a GPR119 agonist and is not a DPP-IVinhibitor. In one aspect of the present invention, the otherpharmaceutically or physiologically acceptable compound is apharmaceutical agent selected from the group consisting of calcium,vitamin D, estrogen, tibolone, selective estrogen receptor modulator(SERM; e.g., raloxifene, tamoxifen), biphosphonate (e.g., etidronate,alendronate, risedronate), calcitonin, 1α-hydroxylated metabolite ofvitamin D, fluoride, thiazide, anabolic steroid, ipriflavone, vitamin K,parathyroid hormone (PTH), strontium, statin, osteoprotererin, EP4receptor selective agonist, cannabinoid receptor type 2 (CB2) selectiveagonist, and p38 MAP kinase inhibitor. (See, e.g., World HealthOrganization Technical Report Series 921 (2003), Prevention andManagement of Osteoporosis.)

In a combination therapy according to the present invention, the GPR119agonist according to the present invention and the DPP-IV inhibitoraccording to the present invention can be administered simultaneously orat separate intervals. When administered simultaneously the GPR119agonist and the DPP-IV inhibitor can be incorporated into a singlepharmaceutical composition or into separate compositions, e.g., theGPR119 agonist in one composition and the DPP-IV inhibitor in anothercomposition. Each of these compositions may be formulated with commonexcipients, diluents or carriers, and compressed into tablets, orformulated elixirs or solutions; and as sustained relief dosage formsand the like. The GPR119 agonist and DPP-IV inhibitor may beadministered via different routes. For example, the GPR119 agonist maybe administered orally via tablet and the DPP-IV inhibitor may beadministered via inhalation.

When separately administered, therapeutically effective amounts of theGPR119 agonist and the DPP-IV inhibitor according to the presentinvention are administered on a different schedule. One may beadministered before the other as long as the time between the twoadministrations falls within a therapeutically effective interval. Atherapeutically effective interval is a period of time beginning whenone of either (a) the GPR119 agonist or (b) the DPP-IV inhibitor isadministered to an individual and ending at the limit of the beneficialeffect in the treatment of the combination of (a) and (b).

In one aspect, the present invention features a composition comprisingor consisting essentially of an amount of a GPR119 agonist according tothe present invention. In one aspect, the present invention features apharmaceutical composition comprising or consisting essentially of anamount of a GPR119 agonist according to the present invention and atleast one pharmaceutically acceptable carrier.

In one aspect, the present invention features a combination comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention features a pharmaceutical combination comprising or consistingessentially of a combination of an amount of a GPR119 agonist accordingto the present invention and an amount of a DPP-IV inhibitor accordingto the present invention, together with at least one pharmaceuticallyacceptable carrier.

In one aspect, the present invention features a composition comprisingor consisting essentially of an amount of a GPR119 agonist according tothe present invention. In one aspect, the present invention features apharmaceutical composition comprising or consisting essentially of anamount of a GPR119 agonist according to the present invention and atleast one pharmaceutically acceptable carrier. The present inventionalso relates to a dosage form of the composition or of thepharmaceutical composition wherein the GPR119 agonist is in an amountsufficient to give an effect in treating or preventing a conditioncharacterized by low bone mass, such as osteoporosis, and/or inincreasing bone mass in an individual.

In one aspect, the present invention features a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention features a pharmaceutical composition comprising or consistingessentially of a combination of an amount of a GPR119 agonist accordingto the present invention and an amount of a DPP-IV inhibitor accordingto the present invention, together with at least one pharmaceuticallyacceptable carrier. The present invention also relates to a dosage formof the composition or of the pharmaceutical composition wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient togive an effect in treating or preventing a condition characterized bylow bone mass, such as osteoporosis, and/or in increasing bone mass inan individual.

In one aspect, the present invention features a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention features a pharmaceutical composition comprising or consistingessentially of a combination of an amount of a GPR119 agonist accordingto the present invention and an amount of a DPP-IV inhibitor accordingto the present invention, together with at least one pharmaceuticallyacceptable carrier. The present invention also relates to a dosage formof the composition or of the pharmaceutical composition wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient togive an effect in treating or preventing a condition characterized bylow bone mass, such as osteoporosis, and/or in increasing bone mass inan individual, and wherein the amount of the GPR119 agonist alone andthe amount of the DPP-IV inhibitor alone are not therapeuticallyeffective in treating or preventing a condition characterized by lowbone mass, such as osteoporosis, and/or in increasing bone mass in theindividual.

In one aspect, the present invention features a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention features a pharmaceutical composition comprising or consistingessentially of a combination of an amount of a GPR119 agonist accordingto the present invention and an amount of a DPP-IV inhibitor accordingto the present invention, together with at least one pharmaceuticallyacceptable carrier. The present invention also relates to a dosage formof the composition or of the pharmaceutical composition wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient togive an effect in treating or preventing a condition characterized bylow bone mass, such as osteoporosis, and/or in increasing bone mass inan individual, and wherein the effect is a synergistic effect.

In one aspect, the present invention relates to a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention relates to a pharmaceutical composition comprising orconsisting essentially of a combination of an amount of a GPR119 agonistaccording to the present invention and an amount of a DPP-IV inhibitoraccording to the present invention, together with at least onepharmaceutically acceptable carrier. The present invention also relatesto a dosage form of the composition or of the pharmaceutical compositionwherein the GPR119 agonist and the DPP-IV inhibitor are in amountssufficient to give an effect in treating or preventing a conditioncharacterized by low bone mass, such as osteoporosis, and/or inincreasing bone mass in an individual, wherein the effect is asynergistic effect, and wherein the amount of the GPR119 agonist aloneand the amount of the DPP-IV inhibitor alone are not therapeuticallyeffective in treating or preventing a condition characterized by lowbone mass, such as osteoporosis, and/or in increasing bone mass in theindividual.

In one aspect, the present invention relates to a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention relates to a pharmaceutical composition comprising orconsisting essentially of a combination of an amount of a GPR119 agonistaccording to the present invention and an amount of a DPP-IV inhibitoraccording to the present invention, together with at least onepharmaceutically acceptable carrier. The present invention also relatesto a dosage form of the composition or of the pharmaceutical compositionwherein the GPR119 agonist and the DPP-IV inhibitor are in amountssufficient to give an effect in treating or preventing a conditioncharacterized by low bone mass, such as osteoporosis, and/or inincreasing bone mass in an individual, wherein the effect given by thecombination of the amount of the GPR119 agonist and the amount of theDPP-IV inhibitor is greater than the effect given by the amount of theGPR119 agonist alone and the effect given by the amount of the DPP-IVinhibitor alone.

In one aspect, the present invention features a composition comprisingor consisting essentially of an amount of a GPR119 agonist according tothe present invention. In one aspect, the present invention features apharmaceutical composition comprising or consisting essentially of anamount of a GPR119 agonist according to the present invention and atleast one pharmaceutically acceptable carrier. The present inventionalso relates to a dosage form of the composition or of thepharmaceutical composition wherein the GPR119 agonist is in an amountsufficient to give an effect in increasing a GIP level in an individual.

In one aspect, the present invention features a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention features a pharmaceutical composition comprising or consistingessentially of a combination of an amount of a GPR119 agonist accordingto the present invention and an amount of a DPP-IV inhibitor accordingto the present invention, together with at least one pharmaceuticallyacceptable carrier. The present invention also relates to a dosage formof the composition or of the pharmaceutical composition wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient togive an effect in increasing a GIP level in an individual.

In one aspect, the present invention features a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention features a pharmaceutical composition comprising or consistingessentially of a combination of an amount of a GPR119 agonist accordingto the present invention and an amount of a DPP-IV inhibitor accordingto the present invention, together with at least one pharmaceuticallyacceptable carrier. The present invention also relates to a dosage formof the composition or of the pharmaceutical composition wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient togive an effect in increasing a GIP level in a subject, and wherein theamount of the GPR119 agonist alone and the amount of the DPP-IVinhibitor alone are not therapeutically effective in increasing a GIPlevel in the individual.

In one aspect, the present invention features a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention features a pharmaceutical composition comprising or consistingessentially of a combination of an amount of a GPR119 agonist accordingto the present invention and an amount of a DPP-IV inhibitor accordingto the present invention, together with at least one pharmaceuticallyacceptable carrier. The present invention also relates to a dosage formof the composition or of the pharmaceutical composition wherein theGPR119 agonist and the DPP-IV inhibitor are in amounts sufficient togive an effect in increasing a GIP level in an individual, and whereinthe effect is a synergistic effect.

In one aspect, the present invention relates to a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention relates to a pharmaceutical composition comprising orconsisting essentially of a combination of an amount of a GPR119 agonistaccording to the present invention and an amount of a DPP-IV inhibitoraccording to the present invention, together with at least onepharmaceutically acceptable carrier. The present invention also relatesto a dosage form of the composition or of the pharmaceutical compositionwherein the GPR119 agonist and the DPP-IV inhibitor are in amountssufficient to give an effect in increasing a GIP level in a subject,wherein the effect is a synergistic effect, and wherein the amount ofthe GPR119 agonist alone and the amount of the DPP-IV inhibitor aloneare not therapeutically effective in increasing a GIP level in theindividual.

In one aspect, the present invention relates to a composition comprisingor consisting essentially of a combination of an amount of a GPR119agonist according to the present invention and an amount of a DPP-IVinhibitor according to the present invention. In one aspect, the presentinvention relates to a pharmaceutical composition comprising orconsisting essentially of a combination of an amount of a GPR119 agonistaccording to the present invention and an amount of a DPP-IV inhibitoraccording to the present invention, together with at least onepharmaceutically acceptable carrier. The present invention also relatesto a dosage form of the composition or of the pharmaceutical compositionwherein the GPR119 agonist and the DPP-IV inhibitor are in amountssufficient to give an effect in increasing a GIP level in a subject,wherein the effect given by the combination of the amount of the GPR119agonist and the amount of the DPP-IV inhibitor is greater than theeffect given by the amount of the GPR119 agonist alone and the effectgiven by the amount of the DPP-IV inhibitor alone.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in anamount to achieve their intended purpose. In some embodiments, apharmaceutical composition of the present invention is understood to beuseful for treating or preventing a condition characterized by low bonemass, such as osteoporosis, or for increasing bone mass in anindividual. Conditions characterized by low bone mass are according tothe present invention. In some embodiments, a pharmaceutical compositionof the present invention is understood to be useful for increasing a GIPlevel in an individual. As relates to the present invention,determination of the amount of a GPR119 agonist or of the amount of acombination of a GPR119 agonist with a DPP-IV inhibitor sufficient toachieve an intended purpose according to the invention is well withinthe capability of those skilled in the art, especially in light of thedetailed disclosure provided herein.

The data obtained from animal studies, including but not limited tostudies using mice, rats, rabbits, pigs, and non-human primates, can beused in formulating a range of dosage for use in humans. In general, oneskilled in the art understands how to extrapolate in vivo data obtainedin an animal model system to another, such as a human. In somecircumstances, these extrapolations may merely be based on the weight ofthe animal model in comparison to another, such as a human; in othercircumstances, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, on whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

An exemplary animal model system is the rat ovariectomy (OVX) bone lossmodel. The ovariectomized rat is an excellent preclinical animal modelthat correctly emulates the important clinical feature of the estrogendepleted human skeleton and the response of therapeutic agents. In thismodel, a therapeutic efficacy is achieved when the bone loss associatedwith ovariectomy is partially or completely prevented. (See, e.g.,Bollag et al, Mol Cell Endocrinol (2001) 177:35-41; and Jee et al, JMusculoskel Neuron Interact (2001) 1:193-207.) In certain embodiments,therapeutic efficacy is achieved when the bone loss associated withovariectomy is at least about 10% prevented, at least about 20%prevented, at least about 30% prevented, at least about 40% prevented,at least about 50% prevented, at least about 60% prevented, at leastabout 70% prevented, at least about 75% prevented, at least about 80%prevented, at least about 85% prevented, at least about 90% prevented,at least about 95% prevented, or 100% prevented.

An additional exemplary animal model system is increase of a blood GIPlevel after glucose challenge in mice. In certain embodiments, the bloodGIP level is a plasma GIP level. In certain embodiments, the GIP levelis a glucose-independent GIP level. In certain embodiments, the GIPlevel is a glucose-dependent GIP level. In certain embodiments, the GIPis total GIP. In certain embodiments, the total GIP is measured using acentrally or C-terminally directed assay. In certain embodiments, theGIP is bioactive GIP. In certain embodiments, the bioactive GIP ismeasured using an N-terminal-specific assay. In certain embodiments, thebioactive GIP has activity for promoting bone formation. In certainembodiments, therapeutic efficacy is achieved when the blood GIP levelis increased by at least about 10%, at least about 25%, at least about50%, at least about 100%, at least about 150%, at least about 200%, atleast about 300%, at least about 400%, or at least about 500%.

Dosage amount and interval may be adjusted in order to provide anintended therapeutic effect. It will be appreciated that the exactdosage of a GPR119 agonist or DPP-IV inhibitor in accordance with thepresent invention will vary depending on the GPR119 agonist, thecombination of a GPR119 agonist and a DPP-IV inhibitor, its potency, themode of administration, the age and weight of the patient and theseverity of the condition to be treated. The exact formulation, route ofadministration and dosage can be chosen by the individual physician inview of the patient's condition. By way of illustration and notlimitation, an amount of a GPR119 agonist and/or an amount of a DPP-IVinhibitor in accordance with the present invention is less than about0.001 mg/kg body weight, less than about 0.005 mg/kg body weight, lessthan about 0.01 mg/kg body weight, less than about 0.05 mg/kg bodyweight, less than about 0.1 mg/kg body weight, less than about 0.5 mg/kgbody weight, less than about 1 mg/kg body weight, less than about 5mg/kg body weight, less than about 10 mg/kg body weight, less than about50 mg/kg body weight, or less than about 100 mg/kg body weight. Incertain embodiments, an amount of a GPR119 agonist and/or an amount of aDPP-IV inhibitor in accordance with the present invention is less thanabout 0.001-100 mg/kg body weight, less than about 0.001-50 mg/kg bodyweight, less than about 0.001-10 mg/kg body weight, less than about0.001-5 mg/kg body weight, less than about 0.001-1 mg/kg body weight,less than about 0.001 to 0.5 mg/kg body weight, less than about0.001-0.1 mg/kg body weight, less than about 0.001-0.05 mg/kg bodyweight, less than about 0.001-0.01 mg/kg body weight, or less than about0.001-0.005 mg/kg body weight.

It is expressly contemplated that a GPR119 agonist and a combination ofa GPR119 agonist and a DPP-IV inhibitor can be used in methods ofpreventing bone loss (e.g., methods of preventing a decrease in bonemass), methods of inhibiting bone loss (e.g., methods of inhibiting adecrease in bone mass), methods of maintaining bone mass, and methods ofpromoting bone formation (e.g., methods of increasing bone mass) in anindividual.

A preferred dosage range for an amount of a GPR119 agonist which can beadministered on a daily or regular basis to achieve desired results is0.001-100 mg/kg (mpk) body mass. Other preferred dosage range is0.001-30 mg/kg body mass. Other preferred dosage range is 0.001-10 mg/kgbody mass. Other preferred dosage range is 0.001-3.0 mg/kg body mass.Other preferred dosage range is 0.001-1.0 mg/kg body mass. Otherpreferred dosage range is 0.001-0.3 mg/kg body mass. Other preferreddosage range is 0.001-0.1 mg/kg body mass. Other preferred dosage rangeis 0.001-0.03 mg/kg body mass. Other preferred dosage range is0.001-0.01 mg/kg body mass. Of course, these daily dosages can bedelivered or administered in small amounts periodically during thecourse of a day. It is noted that these dosage ranges are only preferredranges and are not meant to be limiting to the invention.

A preferred dosage range for an amount of a GPR119 agonist used incombination with a DPP-IV inhibitor for which a combination can beadministered on a daily or regular basis to achieve desired results is0.001-100 mg/kg body mass. Other preferred dosage range is 0.001-30mg/kg body mass. Other preferred dosage range is 0.001-10 mg/kg bodymass. Other preferred dosage range is 0.001-3.0 mg/kg body mass. Otherpreferred dosage range is 0.001-1.0 mg/kg body mass. Other preferreddosage range is 0.001-0.3 mg/kg body mass. Other preferred dosage rangeis 0.001-0.1 mg/kg body mass. Other preferred dosage range is 0.001-0.03mg/kg body mass. Other preferred dosage range is 0.001-0.01 mg/kg bodymass. Of course, these daily dosages can be delivered or administered insmall amounts periodically during the course of a day. It is noted thatthese dosage ranges are only preferred ranges and are not meant to belimiting to the invention.

A preferred dosage range for an amount of a. DPP-IV inhibitor used incombination with a GPR119 agonist for which a combination can beadministered on a daily or regular basis to achieve desired results is0.001-100 mg/kg body mass. Other preferred dosage range is 0.001-30mg/kg body mass. Other preferred dosage range is 0.001-10 mg/kg bodymass. Other preferred dosage range is 0.001-3.0 mg/kg body mass. Otherpreferred dosage range is 0.001-1.0 mg/kg body mass. Other preferreddosage range is 0.001-0.3 mg/kg body mass. Other preferred dosage rangeis 0.001-0.1 mg/kg body mass. Other preferred dosage range is 0.001-0.03mg/kg body mass. Other preferred dosage range is 0.001-0.01 mg/kg bodymass. Of course, these daily dosages can be delivered or administered insmall amounts periodically during the course of a day. It is noted thatthese dosage ranges are only preferred ranges and are not meant to belimiting to the invention.

It is expressly contemplated that, a GPR119 agonist or a combination ofa GPR119 agonist and a DPP-IV inhibitor can be administered on a dailyor regular basis to achieve an increased level of GIP in an individual.In certain embodiments, a GPR119 agonist or a combination of a GPR119agonist and a DPP-IV inhibitor is administered on a daily or regularbasis to achieve an increased blood (e.g., plasma or serum) level of GIPin an individual. In certain embodiments, a GPR119 agonist or acombination of a GPR119 agonist and a DPP-IV inhibitor is administeredon a daily or regular basis to achieve an increased blood (e.g., plasmaor serum) level of GIP in an individual that is 110% to 1000%, 110% to900%, 110% to 800%, 110% to 700%, 110% to 600%, 110% to 500%, 110% to400%, 110% to 300%, 110% to 200%, or 110% to 150% a normal blood levelof GIP (e.g., a normal pre-meal plasma GIP level or a plasma GIP levelbetween the normal pre-meal and post-meal plasma GIP levels) in anindividual or the blood level of GIP in the individual prior totreatment. In certain embodiments, a GPR119 agonist or a combination ofa GPR119 agonist and a DPP-IV inhibitor is administered on a daily orregular basis to achieve an increased blood (e.g., plasma or serum)level of GIP in an individual that is 150% to 1000%, 150% to 900%, 150%to 800%, 150% to 700%, 150% to 600%, 150% to 500%, 150% to 400%, 150% to300%, or 150% to 200% a normal blood level of GIP (e.g., a normalpre-meal plasma GIP level or a plasma GIP level between the normalpre-meal and post-meal plasma GIP levels) in an individual or the bloodlevel of GIP in the individual prior to treatment. In certainembodiments, a GPR119 agonist or a combination of a GPR119 agonist and aDPP-IV inhibitor is administered on a daily or regular basis to achievean increased blood (e.g., plasma or serum) level of GIP in an individualthat is 200% to 1000%, 200% to 900%, 200% to 800%, 200% to 700%, 200% to600%, 200% to 500%, 200% to 400%, or 200% to 300% a normal blood levelof GIP (e.g., a normal pre-meal plasma GIP level or a plasma GIP levelbetween the normal pre-meal and post-meal plasma GIP levels) in anindividual or the blood level of GIP in the individual prior totreatment. In certain embodiments, a GPR119 agonist or a combination ofa GPR119 agonist and a DPP-IV inhibitor is administered on a daily orregular basis to achieve an increased blood (e.g., plasma or serum)level of GIP in an individual that is 250% to 1000%, 250% to 900%, 250%to 800%, 250% to 700%, 250% to 600%, 250% to 500%, 250% to 400%, or 250%to 300% a normal blood level of GIP (e.g., a normal pre-meal plasma GIPlevel or a plasma GIP level between the normal pre-meal and post-mealplasma GIP levels) in an individual or the blood level of GIP in theindividual prior to treatment. In certain embodiments, a GPR119 agonistor a combination of a GPR119 agonist and a DPP-IV inhibitor isadministered on a daily or regular basis to achieve an increased blood(e.g., plasma or serum) level of GIP in an individual that is 300% to1000%, 300% to 900%, 300% to 800%, 300% to 700%, 300% to 600%, 300% to500%, or 300% to 400% a normal blood level of GIP (e.g., a normalpre-meal plasma GIP level or a plasma GIP level between the normalpre-meal and post-meal plasma GIP levels) in an individual or the bloodlevel of GIP in the individual prior to treatment. In certainembodiments, a GPR119 agonist or a combination of a GPR119 agonist and aDPP-IV inhibitor is administered on a daily or regular basis to achievean increased blood (e.g., plasma or serum) level of GIP in an individualthat is 400% to 1000%, 400% to 900%, 400% to 800%, 400% to 700%, 400% to600%, or 400% to 500% a normal blood level of GIP (e.g., a normalpre-meal plasma GIP level or a plasma GIP level between the normalpre-meal and post-meal plasma GIP levels) in an individual or the bloodlevel of GIP in the individual prior to treatment. In certainembodiments, a GPR119 agonist or a combination of a GPR119 agonist and aDPP-IV inhibitor is administered on a daily or regular basis to achievean increased blood (e.g., plasma or serum) level of GIP in an individualthat is 500% to 1000%, 500% to 900%, 500% to 800%, 500% to 700%, or 500%to 600% a normal blood level of GIP (e.g., a normal pre-meal plasma GIPlevel or a plasma GIP level between the normal pre-meal and post-mealplasma GIP levels) in an individual or the blood level of GIP in theindividual prior to treatment. In certain embodiments, the blood (e.g.,plasma or serum) level of GIP is a blood (e.g., plasma or serum) levelof total GIP. In certain embodiments, the blood (e.g., plasma or serum)level of GIP is a blood (e.g., plasma or serum) level of bioactive(active) GIP. It is noted that these ranges of increased blood level ofGIP are exemplary ranges and are not meant to be limiting to theinvention.

It is expressly contemplated that a GPR119 agonist or a combination of aGPR119 agonist and a DPP-IV inhibitor can be administered on a daily orregular basis to achieve an increased level of GIP in an individual. Incertain embodiments, a GPR119 agonist or a combination of a GPR119agonist and a DPP-IV inhibitor is administered on a daily or regularbasis to achieve an increased blood (e.g., plasma or serum) level of GIPin an individual. In certain embodiments, a GPR119 agonist or acombination of a GPR119 agonist and a DPP-IV inhibitor is administeredon a daily or regular basis to achieve a blood (e.g., plasma or serum)level of GIP in an individual within a concentration range that is 100pg/ml to 2000 pg/ml, 100 pg/ml to 1900 pg/ml, 100 pg/ml to 1800 pg/ml,100 pg/ml to 1700 pg/ml, 100 pg/ml to 1600 pg/ml, 100 pg/ml to 1500pg/ml, 100 pg/ml to 1400 pg/ml, 100 pg/ml to 1300 pg/ml, 100 pg/ml to1200 pg/ml, 100 pg/ml to 1100 pg/ml, 100 pg/ml to 1000 pg/ml, 100 pg/mlto 900 pg/ml, 100 pg/ml to 800 pg/ml, 100 pg/ml to 700 pg/ml, 100 pg/mlto 600 pg/ml, 100 pg/ml to 500 pg/ml, 100 pg/ml to 400 pg/ml, 100 pg/mlto 300 pg/ml, or 100 pg/ml to 200 pg/ml. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered on a daily or regular basis to achieve a blood(e.g., plasma or serum) level of GIP in an individual within aconcentration range that is 200 pg/ml to 2000 pg/ml, 200 pg/ml to 1900pg/ml, 200 pg/ml to 1800 pg/ml, 200 pg/ml to 1700 pg/ml, 200 pg/ml to1600 pg/ml, 200 pg/ml to 1500 pg/ml, 200 pg/ml to 1400 pg/ml, 200 pg/mlto 1300 pg/ml, 200 pg/ml to 1200 pg/ml, 200 pg/ml to 1100 pg/ml, 200pg/ml to 1000 pg/ml, 200 pg/ml to 900 pg/ml, 200 pg/ml to 800 pg/ml, 200pg/ml to 700 pg/ml, 200 pg/ml to 600 pg/ml, 200 pg/ml to 500 pg/ml, 200pg/ml to 400 pg/ml, or 200 pg/ml to 300 pg/ml. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered on a daily or regular basis to achieve a blood(e.g., plasma or serum) level of GIP in an individual within aconcentration range that is 300 pg/ml to 2000 pg/ml, 300 pg/ml to 1900pg/ml, 300 pg/ml to 1800 pg/ml, 300 pg/ml to 1700 pg/ml, 300 pg/ml to1600 pg/ml, 300 pg/ml to 1500 pg/ml, 300 pg/ml to 1400 pg/ml, 300 pg/mlto 1300 pg/ml, 300 pg/ml to 1200 pg/ml, 300 pg/ml to 1100 pg/ml, 300pg/ml to 1000 pg/ml, 300 pg/ml to 900 pg/ml, 300 pg/ml to 800 pg/ml, 300pg/ml to 700 pg/ml, 300 pg/ml to 600 pg/ml, 300 pg/ml to 500 pg/ml, or300 pg/ml to 400 pg/ml. In certain embodiments, a GPR119 agonist or acombination of a GPR119 agonist and a DPP-IV inhibitor is administeredon a daily or regular basis to achieve a blood (e.g., plasma or serum)level of GIP in an individual within a concentration range that is 400pg/ml to 2000 pg/ml, 400 pg/ml to 1900 pg/ml, 400 pg/ml to 1800 pg/ml,400 pg/ml to 1700 pg/ml, 400 pg/ml to 1600 pg/ml, 400 pg/ml to 1500pg/ml, 400 pg/ml to 1400 pg/ml, 400 pg/ml to 1300 pg/ml, 400 pg/ml to1200 pg/ml, 400 pg/ml to 1100 pg/ml, 400 pg/ml to 1000 pg/ml, 400 pg/mlto 900 pg/ml, 400 pg/ml to 800 pg/ml, 400 pg/ml to 700 pg/ml, 400 pg/mlto 600 pg/ml, or 400 pg/ml to 500 pg/ml. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered on a daily or regular basis to achieve a blood(e.g., plasma or serum) level of GIP in an individual within aconcentration range that is 500 pg/ml to 2000 pg/ml, 500 pg/ml to 1900pg/ml, 500 pg/ml to 1800 pg/ml, 500 pg/ml to 1700 pg/ml, 500 pg/ml to1600 pg/ml, 500 pg/ml to 1500 pg/ml, 500 pg/ml to 1400 pg/ml, 500 pg/mlto 1300 pg/ml, 500 pg/ml to 1200 pg/ml, 500 pg/ml to 1100 pg/ml, 500pg/ml to 1000 pg/ml, 500 pg/ml to 900 pg/ml, 500 pg/ml to 800 pg/ml, 500pg/ml to 700 pg/ml, or 500 pg/ml to 600 pg/ml. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered on a daily or regular basis to achieve a blood(e.g., plasma or serum) level of GIP in an individual within aconcentration range that is 600 pg/ml to 2000 pg/ml, 600 pg/ml to 1900pg/ml, 600 pg/ml to 1800 pg/ml, 600 pg/ml to 1700 pg/ml, 600 pg/ml to1600 pg/ml, 600 pg/ml to 1500 pg/ml, 600 pg/ml to 1400 pg/ml, 600 pg/mlto 1300 pg/ml, 600 pg/ml to 1200 pg/ml, 600 pg/ml to 1100 pg/ml, 600pg/ml to 1000 pg/ml, 600 pg/ml to 900 pg/ml, 600 pg/ml to 800 pg/ml, or600 pg/ml to 700 pg/ml. In certain embodiments, a GPR119 agonist or acombination of a GPR119 agonist and a DPP-IV inhibitor is administeredon a daily or regular basis to achieve a blood (e.g., plasma or serum)level of GIP in an individual within a concentration range that is 700pg/ml to 2000 pg/ml, 700 pg/ml to 1900 pg/ml, 700 pg/ml to 1800 pg/ml,700 pg/ml to 1700 pg/ml, 700 pg/ml to 1600 pg/ml, 700 pg/ml to 1500pg/ml, 700 pg/ml to 1400 pg/ml, 700 pg/ml to 1300 pg/ml, 700 pg/ml to1200 pg/ml, 700 pg/ml to 1100 pg/ml, 700 pg/ml to 1000 pg/ml, 700 pg/mlto 900 pg/ml, or 700 pg/ml to 800 pg/ml. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered on a daily or regular basis to achieve a blood(e.g., plasma or serum) level of GIP in an individual within aconcentration range that is 800 pg/ml to 2000 pg/ml, 800 pg/ml to 1900pg/ml, 800 pg/ml to 1800 pg/ml, 800 pg/ml to 1700 pg/ml, 800 pg/ml to1600 pg/ml, 800 pg/ml to 1500 pg/ml, 800 pg/ml to 1400 pg/ml, 800 pg/mlto 1300 pg/ml, 800 pg/ml to 1200 pg/ml, 800 pg/ml to 1100 pg/ml, 800pg/ml to 1000 pg/ml, or 800 pg/ml to 900 pg/ml. In certain embodiments,a GPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered on a daily or regular basis to achieve a blood(e.g., plasma or serum) level of GIP in an individual within aconcentration range that is 900 pg/ml to 2000 pg/ml, 900 pg/ml to 1900pg/ml, 900 pg/ml to 1800 pg/ml, 900 pg/ml to 1700 pg/ml, 900 pg/ml to1600 pg/ml, 900 pg/ml to 1500 pg/ml, 900 pg/ml to 1400 pg/ml, 900 pg/mlto 1300 pg/ml, 900 pg/ml to 1200 pg/ml, 900 pg/ml to 1100 pg/ml, or 900pg/ml to 1000 pg/ml. In certain embodiments, the blood (e.g., plasma orserum) level of GIP is a blood (e.g., plasma or serum) level of totalGIP. In certain embodiments, the blood (e.g., plasma or serum) level ofGIP is a blood (e.g., plasma or serum) level of bioactive (active) GIP.In certain embodiments, a GPR119 agonist or a combination of a GPR119agonist and a DPP-IV inhibitor is administered on a daily or regularbasis to achieve a blood (e.g., plasma or serum) level of GIP in anindividual within a concentration range that is 1000 pg/ml to 2000pg/ml, 1000 pg/ml to 1900 pg/ml, 1000 pg/ml to 1800 pg/ml, 1000 pg/ml to1700 pg/ml, 1000 pg/ml to 1600 pg/ml, 1000 pg/ml to 1500 pg/ml, 1000pg/ml to 1400 pg/ml, 1000 pg/ml to 1300 pg/ml, 1000 pg/ml to 1200 pg/ml,or 1000 pg/ml to 1100 pg/ml. In certain embodiments, the blood (e.g.,plasma or serum) level of GIP is a blood (e.g., plasma or serum) levelof total GIP. In certain embodiments, the blood (e.g., plasma or serum)level of GIP is a blood (e.g., plasma or serum) level of bioactive(active) GIP. It is noted that these ranges of blood GIP concentrationare exemplary ranges and are not meant to be limiting to the invention.

In certain embodiments, a GPR119 agonist or a combination of a GPR119agonist and a DPP-IV inhibitor is administered on a daily or regularbasis to achieve an increased level of GIP in an individual in a mannerthat does not lead to down-regulation or to substantial down-regulationof the GIP receptor (decreased levels of GIP receptor protein) in bone(e.g., in femur) (e.g., in osteoblasts). In certain embodiments, thelevel of GIP receptor protein in bone is decreased by less than about90%, less than about 80%, less than about 70%, less than about 60%, lessthan about 50%, less than about 40%, less than about 30%, less thanabout 25%, less than about 20%, less than about 15%, less than about10%, less than about 5%, or less than about 2.5%. In certainembodiments, the level of GIP receptor protein in bone is decreased byless than about 25%, less than about 20%, less than about 15%, less thanabout 10%, less than about 5%, or less than about 2.5%. In certainembodiments, the level of GIP receptor protein in bone is decreased byless than about 10%, less than about 5%, or less than about 2.5%. Incertain embodiments, the level of GIP receptor protein in bone is notdecreased. In certain embodiments, the blood (e.g., plasma or serum)level of GIP is a blood (e.g., plasma or serum) level of total GIP. Incertain embodiments, the blood (e.g., plasma or serum) level of GIP is ablood (e.g., plasma or serum) level of bioactive (active) GIP. Suitableanimals models (e.g., mouse, rat) for assessing an effect of a GIP levelon down-regulation of the GIP receptor in bone are known in the art.Methods for determining down-regulation of the GIP receptor in bone areknown to the skilled artisan and include, e.g., Western blot using anantibody to the GIP receptor. See, e.g., Xie et, al, Bone, 2007.

In certain embodiments, the GPR119 agonist is a GPR119 partial agonist.

In certain embodiments, the GPR119 agonist is a nonendogenous GPR119agonist.

In certain embodiments, administration of a GPR119 agonist or acombination of a GPR119 agonist and a DPP-IV inhibitor is oral.

In certain embodiments related to a combination of a GPR119 agonist anda DPP-IV inhibitor, the GPR119 agonist and the DPP-IV inhibitor areadministered in separate dosage forms or in a single dosage form.

In certain embodiments, a GPR119 agonist or a combination of a GPR119agonist and a DPP-IV inhibitor is administered in a manner that achieveselevation of GIP in an individual in a pulsatile or episodic fashion.Pulsatile or episodic elevation of GIP shall mean that blood (e.g.,plasma or serum) levels of GIP rise from a baseline level to a peaklevel and return to the baseline level at least one time per day. Incertain embodiments, the baseline level of plasma GIP is approximately anormal pre-meal plasma GIP level. In certain embodiments, the baselinelevel of plasma GIP is between the normal pre-meal and post-meal plasmaGIP levels. The skilled artisan would be aware of how to effectpulsatile or episodic elevation of GIP in an individual. In certainembodiments, pulsatile or episodic elevation is achieved byadministering a GPR119 agonist or a combination of a GPR119 agonist anda DPP-IV inhibitor in a manner such that an effect for elevating GIPresulting from the preceding dose completely dissipates before asubsequent dose is administered. In certain embodiments, pulsatile orepisodic elevation of GIP is achieved by administering a GPR119 agonistor a combination of a GPR119 agonist and a DPP-IV inhibitor when plasmaglucose levels rise (e.g., after ingestion of a meal). In certainembodiments, the blood (e.g., plasma or serum) level of GIP is a blood(e.g., plasma or serum) level of total GIP. In certain embodiments, theblood (e.g., plasma or serum) level of GIP is, a blood (e.g., plasma orserum) level of bioactive (active) GIP.

It is expressly contemplated that the dosage interval can relate to thetime at which a meal is ingested. In certain embodiments, a GPR119agonist or a combination of a GPR119 agonist and a DPP-IV inhibitor isadministered before, during or after a meal. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-TVinhibitor is administered before a meal. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered 120 minutes or less prior to a meal. Incertain embodiments, a GPR119 agonist or a combination of a GPR119agonist and a DPP-IV inhibitor is administered 90 minutes or less priorto a meal. In certain embodiments, a GPR119 agonist or a combination ofa GPR119 agonist and a DPP-IV inhibitor is administered 60 minutes orless prior to a meal. In certain embodiments, a GPR119 agonist or acombination of a GPR119 agonist and a DPP-IV inhibitor is administered30 minutes or less prior to a meal. In certain embodiments, a GPR119agonist or a combination of a GPR119 agonist and a DPP-IV inhibitor isadministered 15 minutes or less prior to a meal. In certain embodiments,a GPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered during a meal. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered after a meal. In certain embodiments, a GPR119agonist or a combination of a GPR119 agonist and a DPP-IV inhibitor isadministered 120 minutes or less after a meal. In certain embodiments, aGPR119 agonist or a combination of a GPR119 agonist and a DPP-IVinhibitor is administered 90 minutes or less after a meal. In certainembodiments, a GPR119 agonist or a combination of a GPR119 agonist and aDPP-IV inhibitor is administered 60 minutes or less after a meal. Incertain embodiments, a GPR119 agonist or a combination of a GPR119agonist and a DPP-IV inhibitor is administered 30 minutes or less aftera meal. In certain embodiments, a GPR119 agonist or a combination of aGPR119 agonist and a DPP-IV inhibitor is administered 15 minutes or lessafter a meal. It is noted that these time intervals are exemplary timeintervals and are not meant to be limiting to the invention. In certainembodiments, administration is oral. In certain embodiments related to acombination of a GPR119 agonist and a DPP-IV inhibitor, the GPR119agonist and the DPP-IV inhibitor are administered in separate dosageforms or in a single dosage form. In certain embodiments, the meal is adaily meal such as breakfast, lunch, dinner and the like. In certainembodiments, the meal is a regularly scheduled daily meal such asbreakfast, lunch, dinner and the like. In certain embodiments, a GPR119agonist or a combination of a GPR119 agonist and a DPP-IV inhibitor isadministered before, during or after one or more daily meals such asbreakfast, lunch, dinner and the like. In certain embodiments, a GPR119agonist or a combination of a GPR119 agonist and a DPP-IV inhibitor isadministered before, during or after one or more regularly scheduleddaily meals such as breakfast, lunch, dinner and the like.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. In certain embodiments, saltsderived from inorganic bases include the ammonium, calcium, magnesium,potassium, and sodium salts. Salts in the solid form may exist in morethan one crystal structure, and may also be in the form of hydrates.Salts derived from pharmaceutically acceptable organic non-toxic basesinclude salts of primary, secondary, and tertiary amines, substitutedamines including naturally occurring substituted amines, cyclic amines,and basic ion exchange resins, such as arginine, betaine, caffeine,choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like.

When, the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic,glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic,mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, andthe like. In certain embodiments, such acids include citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids.

Dosage amount and interval may be adjusted individually to provideplasma levels of a GPR119 agonist according to the present inventionand/or of a DPP-IV inhibitor according to the present invention whichachieve an intended therapeutic effect. It is expressly contemplated,e.g., that the dosage interval of a GPR119 agonist either alone or incombination with a DPP-IV inhibitor can be adjusted to coincide withmeals taken by the individual, such as at the time of one or moreregular meals (e.g., at breakfast and/or at lunch and/or at dinner, andthe like). Dosage intervals can also be determined using the value for aselected range of GPR119 agonist concentration or the value for aselected range of DPP-IV inhibitor concentration so as to achieve theintended therapeutic effect. A GPR119 agonist and/or a DPP-IV inhibitorshould be administered using a regimen that maintains plasma levelswithin the selected range of GPR119 agonist concentration and/or DPP-IVinhibitor concentration, respectively, for 10-90% of the time, inparticular embodiment between 30-99% of the time, and in furtherparticular embodiment between 50-90% of the time. In cases of localadministration or selective uptake, the range of GPR119 agonistconcentration and/or the range of DPP-IV inhibitor concentrationproviding the intended therapeutic effect may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe individual being treated, on the individual's weight, the severityof the affliction, the manner of administration, and the judgement ofthe prescribing physician.

In one aspect, the present invention accordingly features a method oftreating or preventing a condition characterized by low bone mass, suchas osteoporosis, or of increasing bone mass comprising administering toan individual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention. In certainembodiments, the composition is a pharmaceutical composition.

In one aspect, the present invention accordingly features a method oftreating or preventing a condition characterized by low bone mass, suchas osteoporosis, or of increasing bone mass comprising administering toan individual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention and an amount of aDPP-IV inhibitor according to the present invention. In certainembodiments, the composition is a pharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass, such asosteoporosis, or of increasing bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention and an amount of aDPP-IV inhibitor according to the present invention. In a relatedaspect, the present invention features said method wherein the GPR119agonist and the DPP-IV inhibitor are administered in amounts sufficientto give an effect in treating or preventing a condition characterized bylow bone mass, such as osteoporosis, and/or in increasing bone mass inan individual, wherein the amount of the GPR119 agonist alone and theamount of the DPP-IV inhibitor alone are not therapeutically effectivein treating or preventing a condition characterized by low bone mass,such as osteoporosis, and/or in increasing bone mass in the individual.In certain embodiments, the composition is a pharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass, such asosteoporosis, or of increasing bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention and an amount of aDPP-IV inhibitor according to the present invention. In a relatedaspect, the present invention features said method wherein the GPR119agonist and the DPP-IV inhibitor are administered in amounts sufficientto give an effect in treating or preventing a condition characterized bylow bone mass, such as osteoporosis, and/or in increasing bone mass inan individual, wherein the effect is a synergistic effect. In certainembodiments, the composition is a pharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in treating or preventing a conditioncharacterized by low bone mass, such as osteoporosis, and/or inincreasing bone mass in an individual, wherein the effect is asynergistic effect, and wherein the amount of the GPR119 agonist aloneand the amount of the DPP-IV inhibitor alone are not therapeuticallyeffective in treating or preventing a condition characterized by lowbone mass, such as osteoporosis, and/or in increasing bone mass in anindividual. In certain embodiments, the composition is a pharmaceuticalcomposition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in treating or preventing a conditioncharacterized by low bone mass, such as osteoporosis, and/or inincreasing bone mass in an individual, wherein the effect given by thecombination of the amount of a GPR119 agonist and the amount of theDPP-IV inhibitor is greater than the effect given by the amount of theGPR119 agonist alone and the effect given by the amount of the DPP-IVinhibitor alone. In certain embodiments, the composition is apharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass, such asosteoporosis, or of increasing bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention. In a related aspect,the present invention features said method wherein the GPR119 agonist isadministered in an amount sufficient to give an effect in increasing aGIP level in the individual. In certain, embodiments, the composition isa pharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass, such asosteoporosis, or of increasing bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention and an amount of aDPP-IV inhibitor according to the present invention. In a relatedaspect, the present invention features said method wherein the GPR119agonist and the DPP-IV inhibitor are administered in amounts sufficientto give an effect in increasing a GIP level in the individual. Incertain embodiments, the composition is a pharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass, such asosteoporosis, or of increasing bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention and an amount of aDPP-IV inhibitor according to the present invention. In a relatedaspect, the present invention features said method wherein the GPR119agonist and the DPP-IV inhibitor are administered in amounts sufficientto give an effect in increasing a GIP level in the individual, andwherein the amount of the GPR119 agonist alone and the amount of theDPP-IV inhibitor alone are not therapeutically effective in increasing aGIP level in the individual. In certain embodiments, the composition isa pharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass, such asosteoporosis, or of increasing bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of acomposition comprising or consisting essentially of an amount of aGPR119 agonist according to the present invention and an amount of aDPP-IV inhibitor according to the present invention. In a relatedaspect, the present invention features said method wherein the GPR119agonist and the DPP-IV inhibitor are administered in amounts sufficientto give an effect in increasing a GIP level in the individual, andwherein the effect is a synergistic effect. In certain embodiments, thecomposition is a pharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in increasing a GIP level in theindividual, wherein the effect is a synergistic effect, and wherein theamount of the GPR119 agonist alone and the amount of the DPP-IVinhibitor alone are not therapeutically effective in increasing a GIPlevel in the individual. In certain embodiments, the composition is apharmaceutical composition.

In one aspect, the present invention relates to a method of treating orpreventing a condition characterized by low bone mass comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a composition comprising or consisting essentiallyof an amount of a GPR119 agonist according to the present invention andan amount of a DPP-IV inhibitor according to the present invention. In arelated aspect, the present invention features said method wherein theGPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to give an effect in increasing a GIP level in theindividual, wherein the effect given by the combination of the amount ofthe GPR119 agonist and the amount of the DPP-IV inhibitor is greaterthan the effect given by the amount of the GPR119 agonist alone and theeffect given by the amount of the DPP-IV inhibitor alone. In certainembodiments, the composition is a pharmaceutical composition.

In certain embodiments, the GIP level is a blood or plasma total GIPlevel. In certain embodiments, the GIP level is a blood or plasmabioactive GIP level.

Therapies of the present invention are useful for increasing boneformation in an individual.

Therapies of the present invention, namely therapies relating to aGPR119 agonist optionally in combination with a DPP-IV inhibitor andincluding the combination therapy relating to a GPR119 agonist and aDPP-IV inhibitor described above are useful in treating or preventing acondition characterized by low bone mass in an individual and inincreasing bone mass in an individual.

In certain embodiments, the individual receiving a therapy of thepresent invention, namely a therapy relating to a GPR119 agonistoptionally in combination with a DPP-IV inhibitor and including thecombination therapy relating to a GPR119 agonist and a DPP-IV inhibitordescribed above is a human and a participant in a study reviewed by agovernmental agency charged with marketing approval for a drug. Incertain, embodiments, the study is a clinical trial. In certainembodiments, the governmental agency is the Food and Drug Administrationof the United States.

Conditions characterized by low bone mass include but are not limited toosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height.In certain embodiments, the condition characterized by low bone mass isosteoporosis. In certain embodiments, the condition characterized by lowbone mass is osteoporosis. In certain embodiments, osteoporosis isprimary osteoporosis. In certain embodiments, osteoporosis is secondaryosteoporosis. Conditions characterized by low bone mass also include butare not limited to long-term complications of osteoporosis such ascurvature of the spine, loss of height and prosthetic surgery. It isunderstood that conditions characterized by low bone mass can beincluded in embodiments individually or in any combination. In certainembodiments, the condition characterized by low bone mass is primaryosteoporosis.

In certain embodiments, the individual in need of increased bone masshas a bone mineral density (BMD) of greater than 1 (T-score<−1), greaterthan or equal to 1.5 (T-score≦−1.5), greater than or equal to 2(T-score≦−2) or greater than or equal to 2.5 (T-score≦−2.5) standarddeviations below the young adult reference mean. In certain embodiments,the individual in need of increased bone mass is in need of treatment ofbone fracture. In certain embodiments, the individual in need oftreatment of a bone fracture has a traumatic bone fracture, a long-termbone fracture, or an osteoporotic bone fracture. In certain embodiments,the individual is in need of treatment for a bone disease. In certainembodiments, the individual in need of treatment for a bone disease hasosteopenia, osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, or loss of height.In certain embodiments, the individual in need of treatment for a bonedisease has osteoporosis. In certain embodiments, osteoporosis isprimary osteoporosis. In certain embodiments, osteoporosis is secondaryosteoporosis. Destructive bone disorders that can be treated accordingto the invention include but are not limited to osteoporosis, primaryosteoporosis, secondary osteoporosis, osteoarthritis, and osteolyticlesions such as those caused by neoplastic disease, radiotherapy, orchemotherapy.

Therapies of the present invention, namely therapies relating to aGPR119 agonist optionally in combination with a DPP-IV inhibitor andincluding the combination therapy relating to a GPR119 agonist and aDPP-IV inhibitor described above are additionally useful in thetreatment of bone fracture. In certain embodiments, the individual inneed of treatment of a bone fracture has a traumatic bone fracture, along-term bone fracture, or an osteoporotic bone fracture.

Therapies of the present invention, namely therapies relating to aGPR119 agonist optionally in combination with a DPP-IV inhibitor andincluding the combination therapy relating to a GPR119 agonist and aDPP-IV inhibitor described above are additionally useful in thetreatment of a bone disease. In certain embodiments, the individual inneed of treatment for a bone disease has osteopenia, osteoporosis,rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar boneloss, osteotomy bone loss, childhood idiopathic bone loss, Paget'sdisease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, or loss of height. In certain embodiments, theindividual in need of treatment for a bone disease has osteoporosis. Incertain embodiments, osteoporosis is primary osteoporosis. In certainembodiments, osteoporosis is secondary osteoporosis. Destructive bonedisorders that can be treated according to the invention include but arenot limited to osteoporosis, primary osteoporosis, secondaryosteoporosis, osteoarthritis, and osteolytic lesions such as thosecaused by neoplastic disease, radiotherapy, or chemotherapy.

Therapies of the present invention, namely therapies relating to aGPR119 agonist optionally in combination with a DPP-IV inhibitor andincluding the combination therapy relating to a GPR119 agonist and aDPP-IV inhibitor described above are additionally useful in enhancingbone healing following facial reconstruction, maxillary reconstruction,mandibular reconstruction, periodontal disease or tooth extraction,enhancing long bone extension, enhancing prosthetic ingrowth orincreasing bone synostosis in an individual.

In certain embodiments, the individual is a vertebrate. In certainembodiments, the individual that is a vertebrate is a fish, anamphibian, a reptile, a bird or a mammal. In certain embodiments, theindividual or vertebrate is a mammal. In certain embodiments, theindividual or vertebrate that is a mammal is a mouse, a rat, a hamster,a rabbit, a pig, a dog, a cat, a horse, a cow, a sheep, a goat, anon-human mammal, a non-human primate or a human. In certainembodiments, the individual is a human. In certain embodiments, thehuman is a post-menopausal woman or a man over the age of 50.

Kits

Also provided by the subject invention are kits for practicing thesubject methods, as described above.

In certain embodiments, the kits at least include a compositioncomprising a GPR119 agonist and instructions for using the components ofthe kit to practice the subject methods, e.g., methods of treating orpreventing a condition characterized by low bone mass, such asosteoporosis, methods of increasing bone mass in an individual, etc. Incertain embodiments, the GPR119 agonist is in dosage form. In certainembodiments, the composition is a pharmaceutical composition.

In certain embodiments, the kits at least include a compositioncomprising a GPR119 agonist and a composition comprising a DPP-IVinhibitor and instructions for using the components of the kit topractice the subject methods, e.g., methods of treating or preventing acondition characterized by low bone mass, such as osteoporosis, methodsof increasing bone mass in an individual, etc. In certain embodiments,the GPR119 agonist and/or the DPP-IV is in dosage form. In certainembodiments, the composition comprising a GPR119 agonist and thecomposition comprising a DPP-IV inhibitor are pharmaceuticalcompositions.

In certain embodiments, the kits at least include a compositioncomprising a GPR119 agonist in combination with a DPP-IV inhibitor andinstructions for using the components of the kit to practice the subjectmethods, e.g., methods of treating or preventing a conditioncharacterized by low bone mass, such as osteoporosis, methods ofincreasing bone mass in an individual, etc. In certain embodiments, theGPR119 agonist in combination with the DPP-IV inhibitor is in dosageform. In certain embodiments, the composition is a pharmaceuticalcomposition.

It is expressly contemplated that the instructions may at least include(as separate or combined instructions) one or both of dosage informationand educational information for using the components of the kit topractice the subject methods. Educational material may relate to saferpractice of the subject methods, greater compliance with practice of thesubject methods, etc. The instructions for practicing the subjectmethods are generally recorded on a suitable recording medium. Forexample, the instructions may be printed on a substrate, such as paperor plastic, etc. As such, the instructions may be present in the kits asa package insert, in the labeling of the container of the kit orcomponents thereof (i.e., associated with the packaging or subpackaging)etc. In other embodiments, the instructions are present as an electronicstorage data file present on a suitable computer readable storagemedium, e.g., CD-ROM, diskette, etc. In yet other embodiments, theactual instructions are not present in the kit, but means for obtainingthe instructions from a remote source, e.g., via the internet, areprovided. An example of this embodiment is a kit that includes a webaddress where the instructions can be viewed and/or from which theinstructions can be downloaded. As with the instructions, this means forobtaining the instructions is recorded on a suitable substrate.

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The foregoing detailed description is given forclearness of understanding only, and no unnecessary limitation should beunderstood therefrom, as modifications within the scope of the inventionmay become apparent to those skilled in the art.

This application claims the benefit of priority from the followingprovisional applications, filed via U.S. Express mail with the UnitedStates Patent and Trademark Office on the indicated dates: U.S.Provisional No. 60/791,613, filed Apr. 11, 2006; U.S. Provisional No.60/834,737, filed Jul. 31, 2006; and U.S. Provisional No. 60/851,244,filed Oct. 12, 2006; the disclosures of each of which are incorporatedherein by reference in their entireties.

Throughout this application, various publications, patents and patentapplications are cited. The disclosures of these publications, patentsand patent applications referenced in this application are hereinincorporated by reference in their entirety into the present disclosure.Citation herein by Applicant of a publication, patent, or patentapplication is not an admission by Applicant of said publication,patent, or patent application as prior art.

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples are to be construedas merely illustrative, and not limitations of the preceding disclosurein any way whatsoever. Those skilled in the art will promptly recognizeappropriate variations from the procedures.

Example 1 Pharmacodynamic Analysis of an Effect of Administration ofGPR119 Agonist on Blood GIP Level in Wild-Type Mice

A. C57blk/6 male mice were fasted for 18 hours, and randomly assignedinto fourteen groups with n=6 for each group. Mice were administered perorally with vehicle (PET; 80% PEG400, 10% ethanol, 10% Tween80) or witha GPR119 agonist in accordance with the present invention (Compound 1Z;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine)at 20 mg/kg, as indicated in FIG. 1A. Thirty minutes after treatment, aglucose bolus at 3 g/kg were delivered per orally, and plasma werecollected at 0 (no glucose bolus), 2, 5, 10, 20, 40 and 60 minutes afterglucose bolus. Plasma GIP levels were determined by using a rodent GIPELISA kit purchased from Linco Research Laboratory [Rat/Mouse GastricInhibitory Polypeptide (Total) ELISA Catalog #EZRMGIP-55K], followinginstructions provided by the supplier. From the results shown in FIG.1A, it is apparent that administration of the GPR119 agonist increasedboth a glucose-dependent and a glucose-independent level of GIP in theblood of the mice. Compound 1Z stimulated plasma total GIP in the mice.Compound 1Z is identical to a compound disclosed in International PatentApplication No. PCT/US2004/001267 (published as WO 2004/065380).

B. C57blk/6 male mice were fasted for 18 hours, and randomly assignedinto fourteen groups with n=6 for each group. Mice were administered perorally with vehicle (20% hydroxypropyl-β-cyclodextrin (HPCD)) or with aGPR119 agonist in accordance with the present invention (Compound 3Z) at10 mg/kg, as indicated in FIG. 1B. Thirty minutes after treatment, aglucose bolus at 3 g/kg were delivered per orally, and plasma werecollected at 0 (no glucose bolus), 5, 10, 20, 60 and 120 minutes afterglucose bolus. Plasma GIP levels were determined by using a rodent GIPELISA kit purchased from Linco Research Laboratory [Rat/Mouse GastricInhibitory Polypeptide (Total) ELISA Catalog #EZRMGIP-55K], followinginstructions provided by the supplier. Statistical analysis wasperformed using Excel program. Mean values of GIP concentration werecalculated based on results with six mice in each group and shown asmean±SEM. From the results shown in FIG. 1B, it is apparent thatadministration of the GPR119 agonist increased both a glucose-dependentand a glucose-independent level of GIP in the blood of the mice.Compound 3Z stimulated plasma total GIP in the mice. Compound 3Z isidentical to a compound disclosed in International Patent ApplicationNo. PCT/US2004/022327 (published as WO 2005/007647).

C. C57blk/6 male mice were fasted for 18 hours, and randomly assignedinto fourteen groups with n=6 for each group. Mice were administered perorally with vehicle (20% hydroxypropyl-β-cyclodextrin (HPCD)) or with aGPR119 agonist in accordance with the present invention (Compound 3Z) at1, 3, or 10 mg/kg. Thirty minutes after treatment, a glucose bolus at 3g/kg was delivered per orally, and plasma were collected at 0 (noglucose bolus) or 5 minutes after glucose bolus. Plasma GIP levels weredetermined by using a rodent GIP ELISA kit purchased from Linco ResearchLaboratory [Rat/Mouse Gastric Inhibitory Peptide (Total) ELISA Catalog#EZRMGIP-55K], following instructions provided by the supplier.Statistical analysis was performed using Excel program. Mean values ofGIP concentration were calculated based on results with six mice in eachgroup and are shown in FIG. 1C. From FIG. 1C, it is apparent that theGPR119 agonist (Compound 3Z) stimulated plasma total GIP in the mice ina dose-dependent manner. Compound 3Z is identical to a compounddisclosed in International Patent Application No. PCT/US2004/022327(published as WO 2005/007647).

Example 2 Effect of Administration of GPR119 Agonist on Blood GIP Levelin GPR119-Deficient (Knockout) Mice Compared to Wild-Type Mice

A. GPR119-deficient male mice and wild-type littermates were fasted for18 hours. Mice were administered per orally with vehicle (PET; 80%PEG400, 10% ethanol, 10% Tween80) or with a GPR119 agonist in accordancewith the present invention (Compound 1Z;(2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine)at 20 mg/kg, as indicated (n=5). Thirty minutes after treatment, blood(100 microliter) was collected via retro orbital vein of the eye (time0) followed by a glucose bolus at 3 g/kg (per orally). Five minutesafter delivering glucose, another blood sample (100 microliter) wascollected (time 5 minutes). Plasma were collected after centrifugationand GIP levels were determined by using a rodent GIP ELISA kit purchasedfrom Linco Research Laboratory [Rat/Mouse Gastric Inhibitory Polypeptide(Total) ELISA Catalog #EZRMGIP-55K], following instructions provided bythe supplier. From the results shown in FIG. 2A, it is apparent thatfunctional GPR119 receptor was necessary for the administered GPR119agonist to increase a glucose-independent level and a glucose-dependentlevel of GIP in the blood of the mice. Compound 1Z stimulated plasmatotal GIP in the wild-type mice. Compound 1Z is identical to a compounddisclosed in International Patent Application No. PCT/US2004/001267(published as WO 2004/065380).

B. GPR119-deficient male mice and wild-type littermates were fasted for18 hours. Mice were administered per orally with vehicle (40%hydroxypropyl-β-cyclodextrin (HPCD)) or with a GPR119 agonist inaccordance with the present invention (Compound 2Z) at 30 mg/kg, asindicated (n=5). Thirty minutes after treatment, blood (100 microliter)was collected via retro orbital vein of the eye (time 0) followed by aglucose bolus at 3 g/kg (per orally). Five minutes after deliveringglucose, another blood sample (100 microliter) was collected (time 5minutes). Plasma were collected after centrifugation and GIP levels weredetermined by using a rodent GIP ELISA kit purchased from Linco ResearchLaboratory [Rat/Mouse Gastric Inhibitory Polypeptide (Total) ELISACatalog #EZRMGIP-55K], following instructions provided by the supplier.Mean values of GIP concentration were calculated based on results withfive mice in each group. From the results shown in FIG. 2B, it isapparent that functional GPR119 receptor was necessary for theadministered GPR119 agonist to increase a glucose-independent level anda glucose-dependent level of GIP in the blood of the mice. Compound 2Zstimulated plasma total GIP in the wild-type mice. Compound 2Z isidentical to a compound disclosed in International Patent ApplicationNo. PCT/US2004/022417 (published as WO 2005/007658).

Example 3 Effect of Administration of GPR119 Agonist in Combination withDPP-IV Inhibitor on Blood GIP Level in Wild-Type Mice

An amount of a GPR119 agonist in combination with an amount of a DPP-IVinhibitor in accordance with the present invention can be shown toincrease a level of GIP in the blood of an individual using the in vivoassay described below.

C57blk/6 male mice are fasted for 18 hours, and randomly assigned intofourteen groups with n=6 for each group. Mice are administered perorally with vehicle (PET; 80% PEG400, 10% ethanol, 10% Tween80) or anamount of a GPR119 agonist in combination with an amount of a DPP-IVinhibitor. The experimental groups are analogous to those of Example 1above. Each of the combined GPR119 agonist and DPP-IV inhibitor is usedat an amount between 0.001 mg/kg body weight and 100 mg/kg body weight.Thirty minutes after treatment, a glucose bolus at 3 g/kg is deliveredper orally, and plasma is collected at 0 (no glucose bolus), 2, 5, 10,20, 40 and 60 minutes after glucose bolus. Plasma GIP levels aredetermined by using a rodent GIP ELISA kit purchased from Linco ResearchLaboratory [Rat/Mouse Gastric Inhibitory Polypeptide (Total) ELISACatalog #EZRMGIP-55K], following instructions provided by the supplier.

The assay may in related version include additional experimental groupswherein the mice are injected with the amount of the GPR119 agonistalone and/or additional experimental groups wherein the mice areinjected with the amount of the DPP-IV inhibitor alone.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inincreasing a blood GIP level in the individual, wherein the amount ofthe GPR119 agonist alone and the amount of the DPP-IV inhibitor aloneare not therapeutically effective in increasing a blood GIP level in theindividual using theforegoing in vivo assay.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inincreasing a blood GIP level in the individual, wherein the effect is asynergistic effect using the foregoing in vivo assay.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inincreasing a blood GIP level in the individual, wherein the effect is asynergistic effect, and wherein the amount of the GPR119 agonist aloneand the amount of a DPP-IV inhibitor alone are not therapeuticallyeffective in increasing a blood GIP level in the individual using theforegoing in vivo assay.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inincreasing a blood GIP level in the individual, wherein the effect givenby the combination of the GPR119 agonist and the DPP-IV inhibitor isgreater than the effect given by the amount of the GPR119 agonist aloneand the effect given by the amount of the DPP-IV inhibitor alone usingthe foregoing in vivo assay.

Example 4 Pharmacodynamic Analysis of an Effect of Administration ofGPR119 Agonist in Combination with DPP-IV Inhibitor on Blood GIP Levelin Wild-Type Mice

An amount of a GPR119 agonist in combination with an amount of a DPP-IVinhibitor in accordance with the present invention was shown to increasea level of GIP in the blood of an individual using the in vivo assay ofExample 3, supra.

C57blk/6 male mice were fasted for 18 hours, and randomly assigned intotwenty-four groups with n=6 for each group. Mice were administered perorally with vehicle (PET; 80% PEG400, 10% ethanol, 10% Tween80), with aDPP-IV inhibitor in accordance with the present invention (AR247810)alone at 1 mg/kg, or with a combination of a GPR119 agonist((2-Fluoro-4-methanesulfonyl-phenyl)-{6-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-1-yl]-5-nitro-pyrimidin-4-yl}-amine)at 10 mg/kg and the DPP-IV inhibitor (AR247810) at 1 mg/kg in accordancewith the present invention, as indicated in FIG. 3. Thirty minutes aftertreatment, a glucose bolus at 3 g/kg were delivered per orally, andplasma were collected at 0 minute, (no glucose bolus), 5 minutes, 10minutes, 20 minutes, 40 minutes, 60 minutes, 90 minutes, and 120 minutesafter glucose bolus. Plasma total GIP levels were determined by using arodent GIP ELISA kit purchased from Linco Research Laboratory [Rat/MouseGastric Inhibitory Polypeptide (Total) ELISA Catalog #EZRMGIP-55K],following instructions provided by the supplier.

From the results shown in FIG. 3, it is apparent that administration ofthe amount of the GPR119 agonist in combination with the amount of theDPP-IV inhibitor in accordance with the present invention consistentlygave an effect in increasing a level of GIP in the blood of in the micegreater than the effect given by the amount of the DPP-IV inhibitoralone.

Example 5 Effect of Administration of GPR119 Agonist on Bone Mass inOvariectomized Rats

A GPR119 agonist in accordance with the present invention can be shownto be effective in treating or preventing a condition characterized bylow bone mass, such as osteoporosis, and/or in increasing bone mass inan individual using the in vivo ovariectomized (OVX) rat model describedbelow [see, e.g., Bollag et al, Mol Cell Endocrinol (2001) 177:35-41].

Twenty virgin female OVX and 20 virgin non-OVX Sprague-Dawley rats(150-175 g), age 8 weeks, are purchased from Harlan Sprague-Dawley, Inc.(Indianapolis, Ind.). Animals are fed ad libitum on a normal commercialpellet diet, Teklab Rodent diet (1.46% calcium), with free access towater. The rats are randomly divided into four weight-matchedexperimental groups and selected to receive per orally vehicle or aGPR119 agonist in accordance with the present invention. Treatment iscontinued on a daily basis for 6 weeks.

-   -   1. Control. Ten non-OVX rats are administered per orally        vehicle.    -   2. Control+Treatment. Ten non-OVX rats are administered per        orally GPR119 agonist.    -   3. OVX. Ten OVX rats are administered per orally vehicle.    -   4. OVX+Treatment. Ten OVX rats are administered per orally        GPR119 agonist.        The rats are weighed daily and length measured at baseline and        again at 6 weeks. Dual energy X-ray absorptiometry (DXA) using a        Hologic QDR 1000/W (Waltham, Mass.) is performed on all animals        prior to initiation of treatment and at 6 weeks, and data is        analyzed using the software Rat Whole Body version 5.53. Bone        mineral density (BMD) is determined at the spine.

The percent change in vertebral bone density after 6 weeks of treatmentis determined. It is shown that administration of a GPR119 agonistattenuates the negative effects of ovariectomy on vertebral bonedensity. Attenuation of the negative effects of ovariectomy on vertebralbone density is indicative of the treatment having efficacy in treatingor preventing a condition characterized by low bone mass, such asosteoporosis, and/or in increasing bone mass in an individual.

Example 6 Effect of Administration of GPR119 Agonist in Combination withDPP-IV Inhibitor on Bone Mass in Ovariectomized Rats

A GPR119 agonist in combination with a DPP-IV inhibitor in accordancewith the present invention can be shown to be effective in treating orpreventing a condition characterized by low bone mass, such asosteoporosis, and/or in increasing bone mass in an individual using thein vivo ovariectomized (OVX) rat model described below [see, e.g.,Bollag et al, Mol Cell Endocrinol (2001) 177:35-41].

Twenty virgin female OVX and 20 virgin non-OVX Sprague-Dawley rats(150-175 g), age 8 weeks, are purchased from Harlan Sprague-Dawley, Inc.(Indianapolis, Ind.). Animals are fed ad libitum on a normal commercialpellet diet, Teklab Rodent diet (1.46% calcium), with free access towater. The rats are randomly divided into four weight-matchedexperimental groups and selected to receive per orally vehicle or aGPR119 agonist in combination with a DPP-IV inhibitor in accordance withthe present invention. Treatment is continued on a daily basis for 6weeks.

-   -   1. Control. Ten non-OVX rats are administered per orally        vehicle.    -   2. Control+Treatment. Ten non-OVX rats are administered per        orally GPR119 agonist in combination with DPP-IV inhibitor.    -   3. OVX. Ten OVX rats are administered per orally vehicle.    -   4. OVX+Treatment. Ten OVX rats are administered per orally        GPR119 agonist in combination with DPP-IV inhibitor.        The rats are weighed daily and length measured at baseline and        again at 6 weeks. Dual energy X-ray absorptiometry (DXA) using a        Hologic QDR 1000/W (Waltham, Mass.) is performed on all animals        prior to initiation of treatment and at 6 weeks, and data is        analyzed using the software Rat Whole Body version 5.53.

The percent change in vertebral bone density after 6 weeks of treatmentis determined. It is shown that administration of a GPR119 agonistattenuates the negative effects of ovariectomy on vertebral bonedensity. Attenuation of the negative effects of ovariectomy on vertebralbone density is indicative of the treatment having efficacy in treatingor preventing a condition characterized by low bone mass, such asosteoporosis, and/or in increasing bone mass in an individual.

The assay may in related version include additional experimental groupswherein the mice are injected with the amount of the GPR119 agonistalone and/or additional experimental groups wherein the mice areinjected with the amount of the DPP-IV inhibitor alone.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inattenuating the negative effects of ovariectomy on vertebral bonedensity, wherein the amount of the GPR119 agonist alone and the amountof the DPP-IV inhibitor alone are not therapeutically effective inattenuating the negative effects of ovariectomy on vertebral bonedensity using the in vivo assay described above.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inattenuating the negative effects of ovariectomy on vertebral bonedensity, wherein the effect is a synergistic effect using the in vivoassay described above.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inattenuating the negative effects of ovariectomy on vertebral bonedensity, wherein the effect is a synergistic effect, and wherein theamount of the GPR119 agonist alone and the amount of a DPP-IV inhibitoralone are not therapeutically effective in attenuating the negativeeffects of ovariectomy on vertebral bone density using the in vivo assaydescribed above.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect inattenuating the negative effects of ovariectomy on vertebral bonedensity, wherein the effect given by the combination of the GPR119agonist and the DPP-IV inhibitor is greater than the effect given by theamount of the GPR119 agonist alone and the effect given by the amount ofthe DPP-IV inhibitor alone using the in vivo assay described above.

Example 7 Effect of Administration of GPR119 Agonist on Bone FractureHealing

A GPR119 agonist in accordance with the present invention can be shownto be effective in treatment of bone fracture using the in vivo assaydescribed below.

Fracture Technique

Sprague-Dawley rats at 3 months of age are anesthetized with Ketamine. A1 cm incision is made on the anteromedial aspect of the proximal part ofthe right tibia or femur. The following describes the tibial surgicaltechnique. The incision is carried through to the bone, and a 1 mm holeis drilled 4 mm proximal to the distal aspect of the tibial tuberosity 2mm medial to the anterior ridge. Intramedullary nailing is performedwith a 0.8 mm stainless steel tube (maximum load 36.3 N, maximumstiffness 61.8 N/mm, tested under the same conditions as the bones). Noreaming of the medullary canal is performed. A standardized closedfracture is produced 2 mm above the tibiofibular junction by three-pointbending using specially designed adjustable forceps with blunt jaws. Tominimize soft tissue damage, care is taken not to displace the fracture.The skin is closed with monofilament nylon sutures. The operation isperformed under sterile conditions. Radiographs of all fractures aretaken immediately after nailing, and rats with fractures outside thespecified diaphyseal area or with displaced nails are excluded. Theremaining animals are divided randomly into the following groups with10-12 animals per each subgroup per time point for testing the fracturehealing. The rats are administered on a daily basis per orally withvehicle or with a GPR119 agonist. The GPR119 agonist is used at anamount between 0.001 mg/kg body weight and 100 mg/kg body weight.Treatment is continued for 10, 20, 40 and 80 days.

At 10, 20, 40 and 80 days, 10-12 rats from each group are anesthetizedwith Ketamine and sacrificed by exsanguination. Both tibiofibular bonesare removed by dissection and all soft tissue is stripped. Bones from5-6 rats for each group are stored in 70% ethanol for histologicalanalysis, and bones from another 5-6 rats for each group are stored in abuffered Ringer's solution (+4° C., pH 7.4) for radiographs andbiomechanical testing which is performed.

Histological Analysis

The methods for histological analysis of fractured bone have beenpreviously published by Mosekilde and Bak [Bone (1993) 14:19-27].Briefly, the fracture site is sawed 8 mm to each side of the fractureline, embedded undecalcified in methymethacrylate, and cut frontalssections on a Reichert-Jung Polycut microtome in 8 μm thick.Masson-Trichome stained mid-frontal sections (including both tibia andfibula) are used for visualization of the cellular and tissue responseto fracture healing with and without treatment. Sirius red stainedsections are used to demonstrate the characteristics of the callusstructure and to differentiate between woven bone and lamellar bone atthe fracture site. The following measurements are performed: (1)fracture gap—measured as the shortest distance between the cortical boneends in the fracture, (2) callus length and callus diameter, (3) totalbone volume area of callus, (4) bony tissue per tissue area inside thecallus area, (5) fibrous tissue in the callus, and (6) cartilage area inthe callus.

Biomechanical Analysis

The methods for biomechanical analysis have been previously published byBak and Andreassen [Calcif Tissue Int (1989) 45:292-297]. Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedure. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

Example 8 Effect of Administration of GPR119 Agonist in Combination withDPP-IV Inhibitor on Bone Fracture Healing

A GPR119 agonist in combination with a DPP-IV inhibitor in accordancewith the present invention can be shown to be effective in treatment ofbone fracture using the in vivo assay described below.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect intreating bone fracture in the individual, wherein the amount of theGPR119 agonist alone and the amount of the DPP-IV inhibitor alone arenot therapeutically effective in treating bone fracture in theindividual using the in vivo assay described below.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect intreating bone fracture in the individual, wherein the effect is asynergistic effect using the in vivo assay described below.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect intreating bone fracture in the individual, wherein the effect is asynergistic effect, and wherein the amount of the GPR119 agonist aloneand the amount of a DPP-IV inhibitor alone are not therapeuticallyeffective in treating bone fracture in the individual using the in vivoassay described below.

It can be shown that a GPR119 agonist and a DPP-IV inhibitor can beprovided in amounts sufficient for the combination to give an effect intreating bone fracture in the individual, wherein the effect given bythe combination of the GPR119 agonist and the DPP-IV inhibitor isgreater than the effect given by the amount of the GPR119 agonist aloneand the effect given by the amount of the DPP-IV inhibitor alone usingthe in vivo assay described below.

Fracture Technique

Sprague-Dawley rats at 3 months of age are anesthetized with Ketamine. A1 cm incision is made on the anteromedial aspect of the proximal part ofthe right tibia or femur. The following describes the tibial surgicaltechnique. The incision is carried through to the bone, and a 1 mm holeis drilled 4 mm proximal to the distal aspect of the tibial tuberosity 2mm medial to the anterior ridge. Intramedullary nailing is performedwith a 0.8 mm stainless steel tube (maximum load 36.3 N, maximumstiffness 61.8 N/mm, tested under the same conditions as the bones). Noreaming of the medullary canal is performed. A standardized closedfracture is produced 2 mm above the tibiofibular junction by three-pointbending using specially designed adjustable forceps with blunt jaws. Tominimize soft tissue damage, care is taken not to displace the fracture.The skin is closed with monofilament nylon sutures. The operation isperformed under sterile conditions. Radiographs of all fractures aretaken immediately after nailing, and rats with fractures outside thespecified diaphyseal area or with displaced nails are excluded. Theremaining animals are divided randomly into the following groups with10-12 animals per each subgroup per time point for testing the fracturehealing. The rats are administered on a daily basis per orally withvehicle or with a GPR119 agonist in combination with a DPP-IV inhibitor.Each of the combined GPR119 agonist and DPP-IV inhibitor is used at anamount between 0.001 mg/kg body weight and 100 mg/kg body weight. Thirtyminutes later, a glucose bolus at 3 g/kg is delivered per orally.Treatment is continued for 10, 20, 40 and 80 days.

At 10, 20, 40 and 80 days, 10-12 rats from each group are anesthetizedwith Ketamine and sacrificed by exsanguination. Both tibiofibular bonesare removed by dissection and all soft tissue is stripped. Bones from5-6 rats for each group are stored in 70% ethanol for histologicalanalysis, and bones from another 5-6 rats for each group are stored in abuffered Ringer's solution (+4° C., pH 7.4) for radiographs andbiomechanical testing which is performed.

Histological Analysis

The methods for histological analysis of fractured bone have beenpreviously published by Mosekilde and Bak [Bone (1993) 14:19-27].Briefly, the fracture site is sawed 8 mm to each side of the fractureline, embedded undecalcified in methymethacrylate, and cut frontalssections on a Reichert-Jung Polycut microtome in 8 μm thick.Masson-Trichome stained mid-frontal sections (including both tibia andfibula) are used for visualization of the cellular and tissue responseto fracture healing with and without treatment. Sirius red stainedsections are used to demonstrate the characteristics of the callusstructure and to differentiate between woven bone and lamellar bone atthe fracture site. The following measurements are performed: (1)fracture gap—measured as the shortest distance between the cortical boneends in the fracture, (2) callus length and callus diameter, (3) totalbone volume area of callus, (4) bony tissue per tissue area inside thecallus area, (5) fibrous tissue in the callus, and (6) cartilage area inthe callus.

Biomechanical Analysis

The methods for biomechanical analysis have been previously published byBak and Andreassen [Calcif Tissue Int (1989) 45:292-297]. Briefly,radiographs of all fractures are taken prior to the biomechanical test.The mechanical properties of the healing fractures are analyzed by adestructive three- or four-point bending procedure. Maximum load,stiffness, energy at maximum load, deflection at maximum load, andmaximum stress are determined.

Example 9 Melanophore Assay for GPR119 Agonist Activity

Melanophores are maintained in culture as reported by Potenza et al[Pigment Cell Research (1992) 5:372-378] and transfected with anexpression vector encoding a GPR119 receptor (e.g., human GPR119,GenBank® Accession No. AAP72125 and alleles thereof) usingelectroporation. Following electroporation, the transfected cells areplated into 96 well plates for the assay. The cells are then allowed togrow for 48 hours in order to both recover from the electroporationprocedure and attain maximal receptor expression levels.

On the assay day, the growth medium on the cells is replaced withserum-free buffer containing 10 nM melatonin. The melatonin acts via anendogenous Gi-coupled GPCR in the melanophores to lower intracellularcAMP levels. In response to lowered cAMP levels, the melanophorestranslocate their pigment to the center of the cell. The net effect ofthis is a significant decrease in the absorbance reading of the cellmonolayer in the well, measured at 600-650 nM.

After a 1-hour incubation in melatonin, the cells become completelypigment-aggregated. At this point a baseline absorbance reading iscollected. Serial dilutions of test compounds are then added to theplate, and compounds having GPR119 agonist activity produce increases inintracellular cAMP levels. In response to these increased cAMP levels,the melanophores translocate their pigment back into the cell periphery.After one hour, stimulated cells are fully pigment-dispersed. The cellmonolayer in the dispersed state absorbs much more light in the 600-650nm range. The measured increase in absorbance compared to the baselinereading allows one to quantitate the degree of receptor stimulation andplot a dose-response curve.

Materials and methods relating to melanophore assay are found in U.S.Pat. Nos. 5,462,856 and 6,051,386, the disclosure of each of which isherein incorporated by reference in its entirety.

Example 10 In Vitro Assay for Inhibition of DPP-IV Activity

Compounds can be evaluated for inhibition of DPP-IV activity using,e.g., the in vitro fluorescent assay described by Leiting et at (BiochemJ (2003) 371:525-532). In this assay, DPP-IV is assayed continuously in100 mM Hepes buffer (pH 7.5) and 0.1 mg/ml of BSA in a total volume of100 μl for 30 min at 37° C., and read using a Spectramax Gemini platereader (Molecular Devices, Sunnyvale, Calif.). The fluorogenic peptideGly-Pro-AMC (where AMC stands for 7-amino-4-methylcoumarin; obtainedfrom Bachem, Torrance, Calif.) is used as DPP-IV substrate. IC₅₀ valuesfor compounds being evaluated are obtained at 50 μM Gly-Pro-AMC, theK_(m) level of Gly-Pro-AMC concentration.

The protease inhibitory activities of DPP-IV inhibitors can be readilydetermined by methods known to those of ordinary skill in the art sincesuitable in vitro assays for measuring protease activity and theinhibition thereof by test compounds are known.

In other exemplary in vitro assay for DPP-IV inhibition, solutions oftest compounds in varying concentrations (≦10 mM final concentration)are prepared in Dimethyl Sulfoxide (DMSO) and then diluted into assaybuffer comprising: 20 mM Tris, pH 7.4; 20 mM KCl; and 0.1 mg/mL BSA.Human DPP-IV (0.1 nM final concentration) is added to the dilutions andpre-incubated for 10 minutes at ambient temperature before the reactionis initiated with A-P-7-amido-4-trifluoromethylcoumarin (AP-AFC; 10 μMfinal concentration). The total volume of the reaction mixture is 10-100μL depending on assay formats used (384 or 96 well plates). The reactionis followed kinetically (excitation λ=400 nm; emission λ=505 nm) for5-10 minutes or an end-point is measured after 10 minutes. Inhibitionconstants (IC₅₀) are calculated from the enzyme progress curves usingstandard mathematical models.

Compounds can also be evaluated for inhibition of DPP-IV activity for afee by a company that provides the service. By way of example, IC₅₀values for DPP-IV inhibition can be obtained for such compounds throughMDS Pharma Services (Catalog #163910; King of Prussia, Pa.) in in vitroassay using recombinant human DPP-IV.

DPP-IV can be human DPP-IV. DPP-IV can be recombinant human DPP-IV.

Example 11 Whole Cell Adenylyl Cyclase Assay for GPR119 Agonist Activity

Cyclic AMP measurements are done with a Flash Plate™ Adenylyl Cyclasekit (New England Nuclear) according to the supplier's protocol. HEK293cells are plated in 15-cm tissue culture dish at 12×10⁶ cells per dishin regular growth medium (DMEM/10% FBS). On the next day, 10 μg ofeither empty vector DNA or expression plasmid DNA are transfected intocells with lipofectamine (Invitrogen, Carlsbad, Calif.) according tomanufacturer's protocol. After 24 hours in culture, transfected cellsare harvested in GIBCO cell dissociation buffer (Cat #13151-014),pelleted by centrifugation for 5 minutes at 1,100 rpm, and carefullyre-suspended into an appropriate volume of Assay Buffer (50% 1×PBS and50% Stimulation Buffer) to give a final cell count at 2×10⁶ cells/ml.Test compounds are prepared in 50 μl Assay Buffer at desired assayconcentration where indicated, and pipetted into wells of the 96-wellFlash Plate. The cell suspension prepared above was then added (50 μlper well). After an incubation time of 60 minutes at room temperature,100 μl of Detection Mix containing tracer [¹²⁵I]-cAMP is then added tothe wells. Plates are incubated for additional 2 hours followed bycounting in a Wallac MicroBeta scintillation counter. Values ofcAMP/well are extrapolated from a standard cAMP curve which is includedon each assay plate.

An increase in cAMP level in GPR119-transfected HEK293 cells over thatin HEK293 cells transfected with empty vector is indicative of a testcompound being a compound that stimulates GPR119 receptor functionality.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptions, or modifications, as come within thescope of the following claims and its equivalents.

1. A method of treating a condition selected from the group consistingof primary osteoporosis, rheumatoid arthritis, osteoarthritis,periodontal disease, alveolar bone loss, osteotomy bone loss, childhoodidiopathic bone loss, Paget's disease, bone loss due to metastaticcancer, osteolytic lesions, curvature of the spine, and loss of height,comprising administering to an individual in need thereof atherapeutically effective amount of a GPR119 agonist.
 2. A method oftreating a condition selected from the group consisting of primaryosteoporosis, rheumatoid arthritis, osteoarthritis, periodontal disease,alveolar bone loss, osteotomy bone loss, childhood idiopathic bone loss,Paget's disease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, and loss of height, comprising administering toan individual in need thereof a therapeutically effective amount of apharmaceutical composition comprising a GPR119 agonist and apharmaceutically acceptable carrier.
 3. A method of treating bonefracture comprising administering to an individual in need thereof atherapeutically effective amount of a GPR119 agonist.
 4. A method oftreating bone fracture comprising administering to an individual in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a GPR119 agonist and a pharmaceuticallyacceptable carrier.
 5. The method of claim 3, wherein the individual hasa traumatic bone fracture, a long-term bone fracture, or an osteoporoticbone fracture.
 6. A method of enhancing bone healing following facialreconstruction, maxillary reconstruction, mandibular reconstruction,periodontal disease or tooth extraction, enhanced long bone extension,enhanced prosthetic ingrowth or increased bone synostosis comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a GPR119 agonist.
 7. A method of enhancing bonehealing following facial reconstruction, maxillary reconstruction,mandibular reconstruction, periodontal disease or tooth extraction,enhanced long bone extension, enhanced prosthetic ingrowth or increasedbone synostosis comprising administering to an individual in needthereof a therapeutically effective amount of a pharmaceuticalcomposition comprising a GPR119 agonist and a pharmaceuticallyacceptable carrier.
 8. The method of claim 1, wherein the GPR119 agonistis administered in an amount sufficient to increase a GIP level in theindividual.
 9. The method of claim 1, wherein the individual is a human.10. The method of claim 1, wherein the GPR119 agonist is an agonist ofhuman GPR119.
 11. The method of claim 1, wherein the GPR119 agonist is asmall molecule.
 12. The method of claim 1, wherein the GPR119 agonisthas an EC₅₀ of less than about 10 μM.
 13. A method of treating acondition characterized by low bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of aGPR119 agonist and a DPP-IV inhibitor.
 14. A method of treating acondition characterized by low bone mass comprising administering to anindividual in need thereof a therapeutically effective amount of apharmaceutical composition comprising a GPR119 agonist and a DPP-IVinhibitor and a pharmaceutically acceptable carrier.
 15. The method ofclaim 13, wherein the condition characterized by low bone mass isselected from the group consisting of osteopenia, osteoporosis,rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar boneloss, osteotomy bone loss, childhood idiopathic bone loss, Paget'sdisease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, and loss of height.
 16. A method of increasingbone mass comprising administering to an individual in need thereof atherapeutically effective amount of a GPR119 agonist and a DPP-IVinhibitor.
 17. A method of increasing bone mass comprising administeringto an individual in need thereof a therapeutically effective amount of apharmaceutical composition comprising a GPR119 agonist and a DPP-IVinhibitor and a pharmaceutically acceptable carrier.
 18. The method ofclaim 16, wherein the individual has a bone mineral density (BMD)greater than 1 standard deviations (T-score<−1) below the young adultreference mean.
 19. A method of treating bone fracture comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a GPR119 agonist and a DPP-IV inhibitor.
 20. Amethod of treating bone fracture comprising administering to anindividual in need thereof a therapeutically effective amount of apharmaceutical composition comprising a GPR119 agonist and a DPP-IVinhibitor and a pharmaceutically acceptable carrier.
 21. The method ofclaim 19, wherein the individual has a traumatic bone fracture, along-term bone fracture, or an osteoporotic bone fracture.
 22. A methodof treating a bone disease comprising administering to an individual inneed thereof a therapeutically effective amount of a GPR119 agonist anda DPP-IV inhibitor.
 23. A method of treating a bone disease comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of a pharmaceutical composition comprising a GPR119agonist and a DPP-IV inhibitor and a pharmaceutically acceptablecarrier.
 24. The method of claim 22, wherein the bone disease isselected from the group consisting of osteopenia, osteoporosis,rheumatoid arthritis, osteoarthritis, periodontal disease, alveolar boneloss, osteotomy bone loss, childhood idiopathic bone loss, Paget'sdisease, bone loss due to metastatic cancer, osteolytic lesions,curvature of the spine, and loss of height.
 25. A method of enhancingbone healing following facial reconstruction, maxillary reconstruction,mandibular reconstruction, periodontal disease or tooth extraction,enhanced long bone extension, enhanced prosthetic ingrowth or increasedbone synostosis comprising administering to an individual in needthereof a therapeutically effective amount of a GPR119 agonist and aDPP-IV inhibitor.
 26. A method of enhancing bone healing followingfacial reconstruction, maxillary reconstruction, mandibularreconstruction, periodontal disease or tooth extraction, enhanced longbone extension, enhanced prosthetic ingrowth or increased bonesynostosis comprising administering to an individual in need thereof atherapeutically effective amount of a pharmaceutical compositioncomprising a GPR119 agonist and a DPP-IV inhibitor and apharmaceutically acceptable carrier.
 27. The method of claim 13, whereinthe GPR119 agonist and the DPP-IV inhibitor are administered in amountssufficient to increase a GIP level in the individual.
 28. The method ofclaim 13, wherein the individual is a human.
 29. The method of claim 13,wherein the GPR119 agonist is an agonist of human GPR119 and/or theDPP-IV inhibitor is an inhibitor of human DPP-IV.
 30. The method ofclaim 13, wherein the GPR119 agonist is a small molecule and/or theDPP-IV inhibitor is a small molecule.
 31. The method of claim 13,wherein the GPR119 agonist has an EC₅₀ of less than about 10 μM and/orthe DPP-IV inhibitor has an IC₅₀ of less than about 10 μM.
 32. Themethod of claim 1, wherein the condition is primary osteoporosis. 33.The method of claim 1, wherein the condition is rheumatoid arthritis.34. The method of claim 1, wherein the condition is osteoarthritis. 35.The method of claim 1, wherein the condition is bone loss due tometastatic cancer.
 36. The method of claim 1, wherein the GPR119 agonistis a selective GPR119 agonist.
 37. The method of claim 1, wherein theGPR119 agonist has a selectivity for GPR119 over corticotrophinreleasing factor-1 (CRF-1) receptor of at least about 100-fold.
 38. Themethod of claim 1, wherein the GPR119 agonist has an EC50 of less thanabout 1 μM.
 39. The method of claim 1, wherein the GPR119 agonist has anEC50 of less than about 100 nM.
 40. The method of claim 1, wherein theGPR119 agonist is orally active.
 41. The method of claim 1, wherein theGPR119 agonist is orally active and has an EC50 of less than about 100nM.
 42. The method of claim 3, wherein the GPR119 agonist isadministered in an amount sufficient to increase a GIP level in theindividual.
 43. The method of claim 3, wherein the individual is ahuman.
 44. The method of claim 3, wherein the GPR119 agonist is anagonist of human GPR119.
 45. The method of claim 3, wherein the GPR119agonist is a small molecule.
 46. The method of claim 3, wherein theGPR119 agonist has an EC₅₀ of less than about 10 μM.
 47. The method ofclaim 3, wherein the GPR119 agonist is a selective GPR119 agonist. 48.The method of claim 3, wherein the GPR119 agonist has a selectivity forGPR119 over corticotrophin releasing factor-1 (CRF-1) receptor of atleast about 100-fold.
 49. The method of claim 3, wherein the GPR119agonist has an EC50 of less than about 1 μM.
 50. The method of claim 3,wherein the GPR119 agonist has an EC50 of less than about 100 nM. 51.The method of claim 3, wherein the GPR119 agonist is orally active. 52.The method of claim 3, wherein the GPR119 agonist is orally active andhas an EC50 of less than about 100 nM.
 53. The method of claim 6,wherein the GPR119 agonist is administered in an amount sufficient toincrease a GIP level in the individual.
 54. The method of claim 6,wherein the individual is a human.
 55. The method of claim 6, whereinthe GPR119 agonist is an agonist of human GPR119.
 56. The method ofclaim 6, wherein the GPR119 agonist is a small molecule.
 57. The methodof claim 6, wherein the GPR119 agonist has an EC₅₀ of less than about 10μM.
 58. The method of claim 6, wherein the GPR119 agonist is a selectiveGPR119 agonist.
 59. The method of claim 6, wherein the GPR119 agonisthas a selectivity for GPR119 over corticotrophin releasing factor-1(CRF-1) receptor of at least about 100-fold.
 60. The method of claim 6,wherein the GPR119 agonist has an EC50 of less than about 1 μM.
 61. Themethod of claim 6, wherein the GPR119 agonist has an EC50 of less thanabout 100 nM.
 62. The method of claim 6, wherein the GPR119 agonist isorally active.
 63. The method of claim 6, wherein the GPR119 agonist isorally active and has an EC50 of less than about 100 nM.
 64. The methodof claim 13, wherein the GPR119 agonist is a selective GPR119 agonist.65. The method of claim 13, wherein the GPR119 agonist has a selectivityfor GPR119 over corticotrophin releasing factor-1 (CRF-1) receptor of atleast about 100-fold.
 66. The method of claim 13, wherein the GPR119agonist has an EC50 of less than about 1 μM.
 67. The method of claim 13,wherein the GPR119 agonist has an EC50 of less than about 100 nM. 68.The method of claim 13, wherein the GPR119 agonist is orally active. 69.The method of claim 13, wherein the GPR119 agonist is orally active andhas an EC50 of less than about 100 nM.
 70. The method of claim 13,wherein the DPP-IV inhibitor is a selective DPP-IV inhibitor.
 71. Themethod of claim 13, wherein the DPP-IV inhibitor is orally active. 72.The method of claim 13, wherein the DPP-IV inhibitor has an IC50 of lessthan about 10 μM.
 73. The method of claim 13, wherein the DPP-IVinhibitor has an IC50 of less than about 1 μM.
 74. The method of claim13, wherein the DPP-IV inhibitor has an IC50 of less than about 100 nM.75. The method of claim 13, wherein the DPP-IV inhibitor is orallyactive and has an IC50 of less than about 100 nM.
 76. The method ofclaim 13, wherein the DPP-IV inhibitor is an inhibitor of human DPP-IV.77. The method of claim 13, wherein the GPR119 agonist is orally activeand has an EC50 of less than about 100 nM, and the DPP-IV inhibitor isorally active and has an IC50 of less than about 100 nM.
 78. The methodof claim 13, wherein the GPR119 agonist has a selectivity for GPR119over corticotrophin releasing factor-1 (CRF-1) receptor of at leastabout 100-fold, and the DPP-IV inhibitor has a selectivity for humanplasma DPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of atleast 100-fold.
 79. The method of claim 13, wherein the DPP-IV inhibitoris: MK-0431:3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;LAF237:(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine; orBMS-477118:(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo[3.1.0]hexane-3-carbonitrile.
 80. The method of claim 15,wherein the condition is osteoporosis.
 81. The method of claim 15,wherein the condition is rheumatoid arthritis.
 82. The method of claim15, wherein the condition is osteoarthritis.
 83. The method of claim 15,wherein the condition is bone loss due to metastatic cancer.
 84. Themethod of claim 16, wherein the GPR119 agonist is a selective GPR119agonist.
 85. The method of claim 16, wherein the GPR119 agonist has aselectivity for GPR119 over corticotrophin releasing factor-1 (CRF-1)receptor of at least about 100-fold.
 86. The method of claim 16, whereinthe GPR119 agonist has an EC50 of less than about 1 μM.
 87. The methodof claim 16, wherein the GPR119 agonist has an EC50 of less than about100 nM.
 88. The method of claim 16, wherein the GPR119 agonist is orallyactive.
 89. The method of claim 16, wherein the GPR119 agonist is orallyactive and has an EC50 of less than about 100 nM.
 90. The method ofclaim 16, wherein the GPR119 agonist and the DPP-IV inhibitor areadministered in amounts sufficient to increase a GIP level in theindividual.
 91. The method of claim 16, wherein the individual is ahuman.
 92. The method of claim 16, wherein the GPR119 agonist is anagonist of human GPR119 and/or the DPP-IV inhibitor is an inhibitor ofhuman DPP-IV.
 93. The method of claim 16, wherein the GPR119 agonist isa small molecule and/or the DPP-IV inhibitor is a small molecule. 94.The method of claim 16, wherein the GPR119 agonist has an EC₅₀ of lessthan about 10 μM and/or the DPP-IV inhibitor has an IC₅₀ of less thanabout 10 μM.
 95. The method of claim 16, wherein the DPP-IV inhibitor isa selective DPP-IV inhibitor.
 96. The method of claim 16, wherein theDPP-IV inhibitor is orally active.
 97. The method of claim 16, whereinthe DPP-IV inhibitor has an IC50 of less than about 10 μM.
 98. Themethod of claim 16, wherein the DPP-IV inhibitor has an IC50 of lessthan about 1 μM.
 99. The method of claim 16, wherein the DPP-IVinhibitor has an IC50 of less than about 100 nM.
 100. The method ofclaim 16, wherein the DPP-IV inhibitor is orally active and has an IC50of less than about 100 nM.
 101. The method of claim 16, wherein theDPP-IV inhibitor is an inhibitor of human DPP-IV.
 102. The method ofclaim 16, wherein the GPR119 agonist is orally active and has an EC50 ofless than about 100 nM, and the DPP-IV inhibitor is orally active andhas an IC50 of less than about 100 nM.
 103. The method of claim 16,wherein the GPR119 agonist has a selectivity for GPR119 overcorticotrophin releasing factor-1 (CRF-1) receptor of at least about100-fold, and the DPP-IV inhibitor has a selectivity for human plasmaDPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least100-fold.
 104. The method of claim 16, wherein the DPP-IV inhibitor is:MK-0431:3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;LAF237:(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine; orBMS-477118:(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo[3.1.0]hexane-3-carbonitrile.
 105. The method of claim 19,wherein the GPR119 agonist is a selective GPR119 agonist.
 106. Themethod of claim 19, wherein the GPR119 agonist has a selectivity forGPR119 over corticotrophin releasing factor-1 (CRF-1) receptor of atleast about 100-fold.
 107. The method of claim 19, wherein the GPR119agonist has an EC50 of less than about 1 μM.
 108. The method of claim19, wherein the GPR119 agonist has an EC50 of less than about 100 nM.109. The method of claim 19, wherein the GPR119 agonist is orallyactive.
 110. The method of claim 19, wherein the GPR119 agonist isorally active and has an EC50 of less than about 100 nM.
 111. The methodof claim 19, wherein the GPR119 agonist and the DPP-IV inhibitor areadministered in amounts sufficient to increase a GIP level in theindividual.
 112. The method of claim 19, wherein the individual is ahuman.
 113. The method of claim 19, wherein the GPR119 agonist is anagonist of human GPR119 and/or the DPP-IV inhibitor is an inhibitor ofhuman DPP-IV.
 114. The method of claim 19, wherein the GPR119 agonist isa small molecule and/or the DPP-IV inhibitor is a small molecule. 115.The method of claim 19, wherein the GPR119 agonist has an EC₅₀ of lessthan about 10 μM and/or the DPP-IV inhibitor has an IC₅₀ of less thanabout 10 μM.
 116. The method of claim 19, wherein the DPP-IV inhibitoris a selective DPP-IV inhibitor.
 117. The method of claim 19, whereinthe DPP-IV inhibitor is orally active.
 118. The method of claim 19,wherein the DPP-IV inhibitor has an IC50 of less than about 10 μM. 119.The method of claim 19, wherein the DPP-IV inhibitor has an IC50 of lessthan about 1 μM.
 120. The method of claim 19, wherein the DPP-IVinhibitor has an IC50 of less than about 100 nM.
 121. The method ofclaim 19, wherein the DPP-IV inhibitor is orally active and has an IC50of less than about 100 nM.
 122. The method of claim 19, wherein theDPP-IV inhibitor is an inhibitor of human DPP-IV.
 123. The method ofclaim 19, wherein the GPR119 agonist is orally active and has an EC50 ofless than about 100 nM, and the DPP-IV inhibitor is orally active andhas an IC50 of less than about 100 nM.
 124. The method of claim 19,wherein the GPR119 agonist has a selectivity for GPR119 overcorticotrophin releasing factor-1 (CRF-1) receptor of at least about100-fold, and the DPP-IV inhibitor has a selectivity for human plasmaDPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least100-fold.
 125. The method of claim 19, wherein the DPP-IV inhibitor is:MK-0431:3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;LAF237:(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine; orBMS-477118:(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo[3.1.0]hexane-3-carbonitrile.
 126. The method of claim 22,wherein the GPR119 agonist is a selective GPR119 agonist.
 127. Themethod of claim 22, wherein the GPR119 agonist has a selectivity forGPR119 over corticotrophin releasing factor-1 (CRF-1) receptor of atleast about 100-fold.
 128. The method of claim 22, wherein the GPR119agonist has an EC50 of less than about 1 μM.
 129. The method of claim22, wherein the GPR119 agonist has an EC50 of less than about 100 nM.130. The method of claim 22, wherein the GPR119 agonist is orallyactive.
 131. The method of claim 22, wherein the GPR119 agonist isorally active and has an EC50 of less than about 100 nM.
 132. The methodof claim 22, wherein the GPR119 agonist and the DPP-IV inhibitor areadministered in amounts sufficient to increase a GIP level in theindividual.
 133. The method of claim 22, wherein the individual is ahuman.
 134. The method of claim 22, wherein the GPR119 agonist is anagonist of human GPR119 and/or the DPP-IV inhibitor is an inhibitor ofhuman DPP-IV.
 135. The method of claim 22, wherein the GPR119 agonist isa small molecule and/or the DPP-IV inhibitor is a small molecule. 136.The method of claim 22, wherein the GPR119 agonist has an EC₅₀ of lessthan about 10 μM and/or the DPP-IV inhibitor has an IC₅₀ of less thanabout 10 μM.
 137. The method of claim 22, wherein the DPP-IV inhibitoris a selective DPP-IV inhibitor.
 138. The method of claim 22, whereinthe DPP-IV inhibitor is orally active.
 139. The method of claim 22,wherein the DPP-IV inhibitor has an IC50 of less than about 10 μM. 140.The method of claim 22, wherein the DPP-IV inhibitor has an IC50 of lessthan about 1 μM.
 141. The method of claim 22, wherein the DPP-IVinhibitor has an IC50 of less than about 100 nM.
 142. The method ofclaim 22, wherein the DPP-IV inhibitor is orally active and has an IC50of less than about 100 nM.
 143. The method of claim 22, wherein theDPP-IV inhibitor is an inhibitor of human DPP-IV.
 144. The method ofclaim 22, wherein the GPR119 agonist is orally active and has an EC50 ofless than about 100 nM, and the DPP-IV inhibitor is orally active andhas an IC50 of less than about 100 nM.
 145. The method of claim 22,wherein the GPR119 agonist has a selectivity for GPR119 overcorticotrophin releasing factor-1 (CRF-1) receptor of at least about100-fold, and the DPP-IV inhibitor has a selectivity for human plasmaDPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least100-fold.
 146. The method of claim 22, wherein the DPP-IV inhibitor is:MK-0431:3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;LAF237:(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine; orBMS-477118:(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo[3.1.0]hexane-3-carbonitrile.
 147. The method of claim 24,wherein the condition is osteoporosis.
 148. The method of claim 24,wherein the condition is rheumatoid arthritis.
 149. The method of claim24, wherein the condition is osteoarthritis.
 150. The method of claim24, wherein the condition is bone loss due to metastatic cancer. 151.The method of claim 25, wherein the GPR119 agonist is a selective GPR119agonist.
 152. The method of claim 25, wherein the GPR119 agonist has aselectivity for GPR119 over corticotrophin releasing factor-1 (CRF-1)receptor of at least about 100-fold.
 153. The method of claim 25,wherein the GPR119 agonist has an EC50 of less than about 1 μM.
 154. Themethod of claim 25, wherein the GPR119 agonist has an EC50 of less thanabout 100 nM.
 155. The method of claim 25, wherein the GPR119 agonist isorally active.
 156. The method of claim 25, wherein the GPR119 agonistis orally active and has an EC50 of less than about 100 nM.
 157. Themethod of claim 25, wherein the GPR119 agonist and the DPP-IV inhibitorare administered in amounts sufficient to increase a GIP level in theindividual.
 158. The method of claim 25, wherein the individual is ahuman.
 159. The method of claim 25, wherein the GPR119 agonist is anagonist of human GPR119 and/or the DPP-IV inhibitor is an inhibitor ofhuman DPP-IV.
 160. The method of claim 25, wherein the GPR119 agonist isa small molecule and/or the DPP-IV inhibitor is a small molecule. 161.The method of claim 25, wherein the GPR119 agonist has an EC₅₀ of lessthan about 10 μM and/or the DPP-IV inhibitor has an IC₅₀ of less thanabout 10 μM.
 162. The method of claim 25, wherein the DPP-IV inhibitoris a selective DPP-IV inhibitor.
 163. The method of claim 25, whereinthe DPP-IV inhibitor is orally active.
 164. The method of claim 25,wherein the DPP-IV inhibitor has an IC50 of less than about 10 μM. 165.The method of claim 25, wherein the DPP-IV inhibitor has an IC50 of lessthan about 1 μM.
 166. The method of claim 25, wherein the DPP-IVinhibitor has an IC50 of less than about 100 nM.
 167. The method ofclaim 25, wherein the DPP-IV inhibitor is orally active and has an IC50of less than about 100 nM.
 168. The method of claim 25, wherein theDPP-IV inhibitor is an inhibitor of human DPP-IV.
 169. The method ofclaim 25, wherein the GPR119 agonist is orally active and has an EC50 ofless than about 100 nM, and the DPP-IV inhibitor is orally active andhas an IC50 of less than about 100 nM.
 170. The method of claim 25,wherein the GPR119 agonist has a selectivity for GPR119 overcorticotrophin releasing factor-1 (CRF-1) receptor of at least about100-fold, and the DPP-IV inhibitor has a selectivity for human plasmaDPP-IV over one or more of PPCE, DPP-II, DPP-8 and DPP-9 of at least100-fold.
 171. The method of claim 25, wherein the DPP-IV inhibitor is:MK-0431:3(R)-Amino-1-[3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one;LAF237:(1-[[3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine; orBMS-477118:(1S,3S,5S)-2-[2(S)-Amino-2-(3-hydroxyadamantan-1-yl)acetyl]-2azabicyclo[3.1.0]hexane-3-carbonitrile.